Flow regulating inhaler device

ABSTRACT

An inhaler device for pulmonary delivery of at least one substance from a drug dose cartridge to an inhaling user, including: a first conduit for conducting a carrier airflow to a proximal opening of a mouthpiece for use by the user; a holder configured to position the dose cartridge within the carrier airflow; and a second conduit for conducting a shunting airflow to the mouthpiece without passing through the dose cartridge position. In some embodiments, a controller connected to a valve controls a rate of carrier airflow, for example by controlling the shunting airflow, based on a sensor indication of airflow rate and a target airflow profile.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/362,883 filed on Nov. 29, 2016, which is a continuation of PCT PatentApplication No. PCT/IL2015/050678 having International Filing Date ofJun. 30, 2015, which claims the benefit of priority under 35 USC §119(e) of U.S. Provisional Patent Application Nos. 62/019,225 filed onJun. 30, 2014, 62/035,588 filed on Aug. 11, 2014, 62/085,772 filed onDec. 1, 2014, 62/086,208 filed on Dec. 2, 2014 and 62/164,710 filed onMay 21, 2015.

PCT Patent Application No. PCT/IL2015/050678 was co-filed on Jun. 30,2015 with PCT Patent Application Nos. PCT/IL2015/050677,PCT/IL2015/050673, PCT/IL2015/050676, PCT/IL2015/050674 andPCT/IL2015/050675. The contents of the above applications are allincorporated by reference as if fully set forth herein in theirentirety.

FIELD AND BACKGROUND OF THE INVENTION

The present disclosure, in some embodiments thereof, relates topulmonary delivery of a substance using a personal inhaler device and,more particularly, but not exclusively, to controlling flow through aninhaler.

U.S. Pat. No. 5,655,520 teaches “A nebulizer is improved by placing aflexible valve in the ambient air inlet tube. Inhalation suction andVenturi effect shut down the flexible valve in proportion to thestrength of the inhalation. Thus, the same output flow rate is obtainedeven with variable strength inhalations. Medications can be properlyadministered by controlled inhalation flow rates. In an alternateembodiment a metered dose inhaler (MDI) is outfitted with a similarflexible valve. Once again the patient is forced to inhale at a constantflow rate, thus causing the medication to seep deeply into the lungs. Inboth embodiments the flexible valve is preferably shaped in a duckbilled fashion with air flow flowing toward the narrow end of the duckbill.”

SUMMARY OF THE INVENTION

According to an aspect of some embodiments, there is provided an inhalerdevice for delivery to an inhaling user of at least one drug substanceemitted from a dose cartridge, the inhaler device comprising: a firstconduit for conducting a carrier airflow to a proximal opening of amouthpiece from which the user inhales; a holder configured to positionthe dose cartridge at a dose cartridge position defined by the holderwithin the carrier airflow of the first conduit; a second conduit,pneumatically coupled to the first conduit, for conducting a shuntingairflow to the mouthpiece without passing the shunting airflow throughthe dose cartridge position; and at least one valve in at least one ofthe first and second conduits; wherein the at least one valve isoperated by a valve controller to control a rate of carrier airflow inresponse to a negative pressure generated by the inhaling user.

According to some embodiments, the inhaler device comprises at least onesensor positioned and configured for detecting at least one parameterindicating a rate of the carrier airflow.

According to some embodiments, the at least one sensor comprises apressure sensor positioned in the first conduit proximal to the dosecartridge position.

According to some embodiments, the valve controller is functionallyconnected to receive an indication of the rate of the carrier airflowfrom the at least one sensor, and to operate the at least one valvebased on the indication of the rate of the carrier airflow and a targetprofile for the carrier airflow.

According to some embodiments, the indicating parameter comprises a rateof the carrier airflow sensed while the second conduit is at leastpartially obstructed.

According to some embodiments, the valve controller is configured tooperate the at least one valve based on a difference between the targetprofile and the rate of the carrier airflow sensed while the secondconduit is at least partially obstructed.

According to some embodiments, the controller is configured to modifythe target profile based on the received indication of the rate ofcarrier airflow.

According to some embodiments, the second conduit is connected to atleast the first conduit at a junction between the dose cartridgeposition and the proximal opening of the mouthpiece, and the junction isconfigured to conduct airflow from the second conduit tocircumferentially surround the carrier airflow.

According to some embodiments, the valve controller is configured tosubstantially reduce a total rate of airflow to the user for anintermediate period after a first period of airflow.

According to some embodiments, the substantial reduction in the rate oftotal airflow is to no more than 50% of the total rate of airflow duringthe first period of airflow.

According to some embodiments, the bypass airflow through the thirdconduit is controlled by a bypass valve.

According to some embodiments, the third conduit comprises a pluralityof tracts.

According to some embodiments, the inhaler device comprises a bypassvalve controller functionally connected to operate the bypass valve tocontrol airflow through the third conduit.

According to some embodiments, the valve controller and/or bypass valvecontroller are configured to substantially reduce a total rate ofairflow to the user for an intermediate period after a first period ofairflow, and then open at least the third conduit.

According to some embodiments, a summed cross-sectional area of theproximal openings of the first and third conduits is at least 25% largerthan the proximal opening of the first conduit.

According to some embodiments, a minimal cross section through which theflow passes to the user along the third conduit is at least 25% largerthan a minimal cross section through which the flow passes to the userthrough the first conduit.

According to some embodiments, the at least one valve and at least onebypass valve comprise a plurality of valve apertures arranged on amounting movable at least from a first position to a second position,such that moving to the second position aligns a valve aperture to closeof one of the conduits, while also aligning a valve aperture to at leastpartially open another of the conduits.

According to some embodiments, the mounting comprises at least onerotating disc having at least one valve aperture passing therethrough,and the rotating disc is rotatable at least from the first position tothe second position to change the alignment of the aperture to theconduit.

According to some embodiments, the mounting comprises: at least oneinner tube having apertures into the conduits; and at least one outertube having a wall surrounding the inner tube and having the at leastone valve aperture through the wall of the at least one outer tube;wherein the at least one outer tube and the at least one inner tube aremovable with respect to the other at least from the first position tothe second position to change the alignment of the apertures to theconduits.

According to some embodiments, the at least one outer tube comprises twoseparately movable outer tubes; and wherein moving one of the twoseparately movable outer tubes controls the degree of opening of oneconduit, and moving the other controls the degree of opening of anotherconduit.

According to some embodiments, the inhaler device comprises a heatingassembly configured to heat material of the drug dose cartridgecomprising the at least one drug substance to vaporize the at least onedrug substance from the material, wherein the released vapors flow intothe first conduit and enter the carrier airflow.

According to some embodiments, the heating assembly comprises anelectrode configured to apply an electric current to an electricallyresistive heating element of the dose cartridge, when the dose cartridgeis positioned by the holder.

According to some embodiments, the inhaler device comprises: at leastone sensor positioned and configured for detecting at least oneparameter indicating a rate of the carrier airflow; and a heatingcontroller functionally connected to control heating of the material ofthe drug dose cartridge, based on the at least one parameter indicatingthe rate of carrier airflow.

According to some embodiments, the heating controller is configured tostop heating if the rate of carrier airflow drops below a threshold.

According to some embodiments, the heating controller is functionallyconnected to receive an indication of the temperature from thetemperature sensor, and to operate the at least one valve based on theindication of the temperature.

According to some embodiments, the valve controller operates the atleast one valve to reduce the carrier airflow if the temperature fallsbelow a threshold.

According to some embodiments, the target profile comprises a constantflow rate through the first conduit and the dose cartridge position forat least a certain period.

According to some embodiments, the heating controller is configured toactivate drug substance release when commencement of inhalation by theuser is detected or when the rate of carrier airflow is above athreshold.

According to some embodiments, at least the valve controller isconfigured to communicate with one or more of a user interface and aphysician interface.

According to some embodiments, the at least one valve is operable by thevalve controller based on one or more of: a flow rate of inhalation, aflow rate through the dose cartridge position, and a defined time from adetected or estimated event.

According to some embodiments, the inhaler device comprises a fanpositioned to affect carrier airflow through the first conduit.

According to some embodiments, a fan controller is functionallyconnected to operate the fan to induce airflow based on the indicationof the rate of carrier airflow from the sensor and a target profile forthe carrier airflow.

According to some embodiments, the at least one valve comprises a valvepositioned along the first conduit.

According to some embodiments, the at least one valve comprises a valvepositioned along the second conduit configured to at least partiallyclose to limit a rate of shunting airflow, and thereby to affect therate of carrier airflow.

According to some embodiments, the valve controller comprises a portionof the at least one valve mechanically configured to adjust a degree ofopening of the at least one valve based on at least one of the shuntingairflow and the carrier airflow.

According to some embodiments, the holder positions the dose cartridgesuch that at least 90% of the carrier airflow through the first conduitpasses through the dose cartridge.

According to some embodiments, the second conduit is connected to thefirst conduit at a junction located between the dose cartridge positionand the proximal opening of the mouthpiece.

According to some embodiments, at least one of the first and secondconduits comprises a plurality of airflow tracts.

According to an aspect of some embodiments, there is provided an inhalerdevice for delivery to an inhaling user of at least one drug substanceemitted from a dose cartridge, the inhaler device comprising: an atleast first conduit for conducting at least a carrier airflow to aproximal opening of a mouthpiece from which the user inhales; a holderconfigured to position the dose cartridge at a dose cartridge positiondefined by the holder within the carrier airflow of the at least firstconduit; a bypass conduit configured to conduct a bypass airflow to theproximal opening of the mouthpiece through a path separated from the atleast first conduit; and a controller configured for controlling atleast the bypass airflow during a single inhalation such that the rateof total airflow to the proximal opening of the mouthpiece in a firstinhalation period is significantly less than a rate of total airflow tothe proximal opening of the mouthpiece in a later inhalation period.

According to some embodiments, the rate of total airflow in the laterinhalation period is at least 100% larger than during the firstinhalation period.

According to some embodiments, the controller is configured to controlflow through the device during a period intermediate to the firstinhalation period and the later inhalation period such that a total rateof airflow to the proximal opening of the mouthpiece during theintermediate period is significantly lower than in the first inhalationperiod.

According to some embodiments, the rate of total airflow in the firstinhalation period is at least 100% larger than during the intermediateinhalation period.

According to some embodiments, the bypass conduit is connected to thefirst conduit at a junction between the dose cartridge position and theproximal opening of the mouthpiece, and the junction is configured toconduct the bypass airflow to circumferentially surround the carrierairflow.

According to an aspect of some embodiments, there is provided an inhalerdevice for delivery to an inhaling user of at least one drug substanceemitted from a dose cartridge, the inhaler device comprising: an atleast first conduit for conducting at least a carrier airflow to aproximal opening of a mouthpiece from which the user inhales; a holderconfigured to position the dose cartridge at a dose cartridge positiondefined by the holder within the carrier airflow of the at least firstconduit; a bypass conduit configured to conduct a bypass airflow to theproximal opening of the mouthpiece through a path separated from the atleast first conduit; and a controller configured for controlling atleast the bypass airflow and the carrier airflow during a singleinhalation such that the rate of total airflow to the proximal openingof the mouthpiece in an intermediate inhalation period is significantlyless than a rate of total airflow to the proximal opening of themouthpiece during both a later and an earlier inhalation period.

According to an aspect of some embodiments, there is provided a methodof pulmonary delivery of at least one drug substance from a heated drugdose to a user inhaling from an inhaler device, the method comprising:estimating a rate of release of the drug substance from the heated drugdose to an inhalation-induced carrier airflow passing the drug dosecartridge; controlling at least one of the heating of the drug dose andthe rate of carrier airflow such that the drug substance release matchesa target profile of drug substance release.

According to some embodiments, estimating the rate of release comprisesestimating a rate of carrier airflow through the drug dose cartridge.

According to some embodiments, the rate of carrier airflow is adjustedby dynamically controlling an inhalation-induced shunting airflow whichbypasses the drug dose cartridge.

According to some embodiments, the shunting airflow is conducted tocircumferentially surround the carrier airflow, such that airflowcomprising a relatively high drug substance concentration is surroundedby airflow comprising a lower drug substance concentration.

According to some embodiments, the method comprises estimating a totalinhalation rate by limiting airflow in the device to carrier airflow,such that the estimated rate of carrier airflow is equivalent to a totalinhalation flow rate, and controlling to match the target profile ofdrug substance release based on the estimated total inhalation flowrate.

According to some embodiments, a heating pattern applied to the drugdose is adjusted to match a target profile of drug substance release.

According to some embodiments, adjustment of the heating patternincludes controlling at least one of a rate of heating, a frequency ofapplying heating, a target temperature and a period of time in which oneor more given temperatures are maintained.

According to some embodiments, a target profile of drug substancerelease is at least partially specified by heating of the drug dose as afunction of the rate of carrier airflow.

According to some embodiments, a target profile of drug substancerelease is at least partially specified by the rate of carrier airflowas a function of the heating of the drug dose.

According to some embodiments, the controlling comprises modifying apressure differential across the drug dose cartridge.

According to some embodiments, the controlling comprises adjusting theopening of one or more valves.

According to some embodiments, the target profile of drug substancerelease is at least partially specified in terms of a rate of carrierairflow.

According to some embodiments, the specified rate of carrier airflowcomprises a constant rate of carrier airflow for a certain period.

According to some embodiments, the target profile of drug substancerelease is at least partially specified in terms of the heating of thedrug dose.

According to some embodiments, the specified heating of the drug dosecomprises maintaining a drug dose temperature for a certain period.

According to some embodiments, the method comprises modifying the targetprofile during while the user is inhaling.

According to some embodiments, the heated drug dose comprises abotanical substance, and the heating is applied to vaporize the at leastone drug substance.

According to some embodiments, the botanical substance comprisescannabis, and the at least one drug substance comprises THC.

According to some embodiments, the method comprises flushing drug doseresidues from at least one of a conduit of the inhaler device and a dosecartridge by allowing only carrier airflow through the device.

According to some embodiments, the method comprises flushing drug doseresidues by allowing only carrier airflow for a period after heating ofthe material is stopped.

According to an aspect of some embodiments, there is provided an inhalerdevice for providing to an inhaling user a flow-based status indication,the inhaler device comprising: at least one conduit for conductingairflow to a mouthpiece from which the user inhales; at least one valveoperable to modulate resistance to the airflow conducted through theconduit; and a controller functionally connected to the control thevalve to generate a pattern of airflow modulations indicating a statusof the inhaler device to the user.

According to some embodiments, the pattern of airflow modulationsindicates successful operation of the inhaler.

According to an aspect of some embodiments, there is provided a methodof manipulating flow through an inhaler device to provide arespiration-based indication to a user inhaling through the inhalerdevice, comprising: allowing a first period of airflow through theinhaler device during an inhalation; at least partially obstructing theairflow so that a reduction in flow is sensed by the user; allowing asecond period of less obstructed airflow through the inhaler deviceduring a continuation of the same inhalation.

According to some embodiments, airflow during the first period carries adrug substance from the inhaler to the pulmonary system of the user, andwherein airflow during the second period advances a drug substanceinhaled during the first period deeper within the pulmonary system.

According to some embodiments, a rate of airflow during the first periodis controlled based on a target profile of flow through a drug dosecartridge carrying the drug substance and held within the inhalerdevice.

According to some embodiments, the releasing is ceased before theobstructing.

According to some embodiments, a rate of airflow during the secondperiod is at least 50% greater than during the first period.

According to some embodiments, a sequence of flow manipulationsindicates to the user that a use session is completed.

According to some embodiments, the device is configured to provide theuser with an additional audio, visual and/or tactile indication that ause session is completed.

According to some embodiments, at least one of the allowing a firstperiod of airflow, obstructing the airflow and allowing a second periodof less obstructed airflow is performed such that a total volume of flowreaching the user during the second period is larger than a volume of ananatomical dead space of the user.

According to some embodiments, the period of obstructing is selectedaccording to a sensed parameter of the airflow during the first period.

According to some embodiments, the sensed parameter comprises a rate ofairflow.

According to some embodiments, the period of obstructing is extendedwhen a low inhalation flow rate is sensed during the first period.

According to some embodiments, the length of the period of obstructingis based on allowing inhalation effort measured during the first periodto continue long enough that a negative pressure develops causing acalculated minimum volume to be inhaled once airflow resumes in thesecond period.

According to some embodiments, the degree of obstructing is selectedaccording to a sensed parameter of the pressure during the obstructionperiod.

According to some embodiments, the at least partial obstructing of theairflow is increased when a sensed parameter of the pressure during theobstruction period indicates an inhalation force below a threshold.

According to some embodiments, the at least partially obstructing theairflow is performed for a period of between 5 and 400 msec.

According to an aspect of some embodiments, there is provided a inhalerdevice comprising: at least one inner tube comprising a wall having atleast one aperture in pneumatic communication with a central conduitextending longitudinally within the inner tube; and at least one outertube having a wall surrounding at least a portion of the at least oneinner tube and having at least one aperture through the wall of the atleast one outer tube; wherein the at least one outer tube and the atleast one inner tube are movable with respect to each other at leastfrom a first position to a second position to change the alignment ofthe apertures in the inner and outer tubes, such that moving to thesecond position moves an outer tube aperture away from alignment with aninner tube aperture to reduce an opening leading to the central conduit,while also aligning an outer tube aperture with an inner tube apertureto increase an opening leading to the central conduit.

According to some embodiments, the inhaler device comprises a pluralityof holders.

According to some embodiments, the first conduit comprises a pluralityof drug conduit tracts, and the plurality of holders comprises holderslocated in corresponding drug conduit tracts.

According to some embodiments, the plurality of holders comprises atleast two holders located in a common drug conduit tract.

According to some embodiments, the holder positions the dose cartridgewithin the first conduit such that such that the electrode of theheating assembly is sealed from the carrier airflow.

According to some embodiments, the holder positions the dose cartridgesuch that substantially all of the carrier airflow through the firstconduit passes through the dose cartridge.

According to an aspect of some embodiments, there is provided an inhalerdevice for delivery to an inhaling user of at least one drug substanceemitted from a dose cartridge, the inhaler device comprising: a holderconfigured to position the dose cartridge at a dose cartridge positiondefined by the holder, the defined position being such that the leastone drug substance emitted from the dose cartridge enters a carrierairflow; a first conduit for conducting the carrier airflow from thedose cartridge position to a proximal opening of a mouthpiece from whichthe user inhales; a second conduit, pneumatically coupled to the firstconduit, for conducting a shunting airflow to the mouthpiece withoutpassing the shunting airflow through the dose cartridge position; and atleast one valve in at least one of the first and second conduits;wherein the at least one valve is operated by a valve controller tocontrol a rate of carrier airflow in response to a negative pressuregenerated by the inhaling user.

According to an aspect of some embodiments, there is provided an inhalerdevice for delivery to an inhaling user of at least one drug substanceemitted from a dose cartridge, the inhaler device comprising: a holderconfigured to position the dose cartridge at a dose cartridge positiondefined by the holder, the defined position being such that the leastone drug substance emitted from the dose cartridge enters a carrierairflow; a first conduit for conducting the carrier airflow from thedose cartridge position to a proximal opening of a mouthpiece from whichthe user inhales; and a second conduit, connected to the first conduitat a junction between the dose cartridge position and the proximalopening of the mouthpiece, for conducting a shunting airflow to themouthpiece without passing the shunting airflow through the dosecartridge position; wherein the junction is configured to conductairflow from the second conduit to circumferentially surround thecarrier airflow.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, examples formethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

As will be appreciated by one skilled in the art, aspects of the presentinvention may be embodied as a system, method or computer programproduct. Accordingly, aspects of the present invention may take the formof an entirely hardware embodiment, an entirely software embodiment(including firmware, resident software, micro-code, etc.) or anembodiment combining software and hardware aspects that may allgenerally be referred to herein as a “circuit,” “module” or “system.”Furthermore, some embodiments of the present invention may take the formof a computer program product embodied in one or more computer readablemedium(s) having computer readable program code embodied thereon.Implementation of the method and/or system of some embodiments of theinvention can involve performing and/or completing selected tasksmanually, automatically, or a combination thereof. Moreover, accordingto actual instrumentation and equipment of some embodiments of themethod and/or system of the invention, several selected tasks could beimplemented by hardware, by software or by firmware and/or by acombination thereof, e.g., using an operating system.

For example, hardware for performing selected tasks according to someembodiments of the invention could be implemented as a chip or acircuit. As software, selected tasks according to some embodiments ofthe invention could be implemented as a plurality of softwareinstructions being executed by a computer using any suitable operatingsystem. One or more tasks according to some embodiments of method and/orsystem as described herein are performed by a data processor, such as acomputing platform for executing a plurality of instructions.Optionally, the data processor includes a volatile memory for storinginstructions and/or data and/or a non-volatile storage, for example, amagnetic hard-disk and/or removable media, for storing instructionsand/or data. Optionally, a network connection is provided as well. Adisplay and/or a user input device such as a keyboard or mouse areoptionally provided as well.

Any combination of one or more computer readable medium(s) may beutilized for some embodiments of the invention. The computer readablemedium may be a computer readable signal medium or a computer readablestorage medium. A computer readable storage medium may be, for example,but not limited to, an electronic, magnetic, optical, electromagnetic,infrared, or semiconductor system, apparatus, or device, or any suitablecombination of the foregoing. More specific examples (a non-exhaustivelist) of the computer readable storage medium would include thefollowing: an electrical connection having one or more wires, a portablecomputer diskette, a hard disk, a random access memory (RAM), aread-only memory (ROM), an erasable programmable read-only memory (EPROMor Flash memory), an optical fiber, a portable compact disc read-onlymemory (CD-ROM), an optical storage device, a magnetic storage device,or any suitable combination of the foregoing. In the context of thisdocument, a computer readable storage medium may be any tangible mediumthat can contain, or store a program for use by or in connection with aninstruction execution system, apparatus, or device.

A computer readable signal medium may include a propagated data signalwith computer readable program code embodied therein, for example, inbaseband or as part of a carrier wave. Such a propagated signal may takeany of a variety of forms, including, but not limited to,electro-magnetic, optical, or any suitable combination thereof. Acomputer readable signal medium may be any computer readable medium thatis not a computer readable storage medium and that can communicate,propagate, or transport a program for use by or in connection with aninstruction execution system, apparatus, or device.

Program code embodied on a computer readable medium and/or data usedthereby may be transmitted using any appropriate medium, including butnot limited to wireless, wireline, optical fiber cable, RF, etc., or anysuitable combination of the foregoing.

Computer program code for carrying out operations for some embodimentsof the present invention may be written in any combination of one ormore programming languages, including an object oriented programminglanguage such as Java, Smalltalk, C++ or the like and conventionalprocedural programming languages, such as the “C” programming languageor similar programming languages. The program code may execute entirelyon the user's computer, partly on the user's computer, as a stand-alonesoftware package, partly on the user's computer and partly on a remotecomputer or entirely on the remote computer or server. In the latterscenario, the remote computer may be connected to the user's computerthrough any type of network, including a local area network (LAN) or awide area network (WAN), or the connection may be made to an externalcomputer (for example, through the Internet using an Internet ServiceProvider).

Some embodiments of the present invention may be described below withreference to flowchart illustrations and/or block diagrams of methods,apparatus (systems) and computer program products according toembodiments of the invention. It will be understood that each block ofthe flowchart illustrations and/or block diagrams, and combinations ofblocks in the flowchart illustrations and/or block diagrams, can beimplemented by computer program instructions. These computer programinstructions may be provided to a processor of a general purposecomputer, special purpose computer, or other programmable dataprocessing apparatus to produce a machine, such that the instructions,which execute via the processor of the computer or other programmabledata processing apparatus, create means for implementing thefunctions/acts specified in the flowchart and/or block diagram block orblocks.

These computer program instructions may also be stored in a computerreadable medium that can direct a computer, other programmable dataprocessing apparatus, or other devices to function in a particularmanner, such that the instructions stored in the computer readablemedium produce an article of manufacture including instructions whichimplement the function/act specified in the flowchart and/or blockdiagram block or blocks.

The computer program instructions may also be loaded onto a computer,other programmable data processing apparatus, or other devices to causea series of operational steps to be performed on the computer, otherprogrammable apparatus or other devices to produce a computerimplemented process such that the instructions which execute on thecomputer or other programmable apparatus provide processes forimplementing the functions/acts specified in the flowchart and/or blockdiagram block or blocks.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example, and for purposes ofillustrative discussion of embodiments of the invention. In this regard,the description taken with the drawings makes apparent to those skilledin the art how embodiments of the invention may be practiced.

In the drawings:

FIGS. 1A-1B are schematic flowcharts of general (FIG. 1A) and detailed(FIG. 1B) methods for pulmonary delivery of one or more drug substancesto a user using an inhaler device, according to some embodiments;

FIG. 2 is a schematic diagram of controlled flow through an inhalerdevice, according to some embodiments;

FIG. 3 is a schematic illustration of components of a flow controlsystem, for example as incorporated within an inhaler device, accordingto some embodiments;

FIGS. 4A-4E illustrate flow regulation at some time points following anindication of inhalation, according to some embodiments;

FIG. 5 is a schematic graph of a flow regime for pulmonary delivery of adrug substance, according to some embodiments;

FIG. 6 is a schematic cross section of a flow regime through a conduitof an inhaler device configured for reducing adherence of drug doseresidue to the inner walls of the conduit, according to someembodiments;

FIG. 7 is a flow chart of a mechanical operation of an inhaler device,according to some embodiments;

FIG. 8 illustrates a longitudinal cross section view of an inhalerdevice, according to some embodiments;

FIGS. 9A-9B are a front view cross section of a mouthpiece of an inhalerdevice (FIG. 9A) and a longitudinal cross section of the mouthpiece(FIG. 9B), according to some embodiments;

FIGS. 10A-10C are isometric, partially cross-sectional views of themouthpiece during operating stages of the inhaler device, according tosome embodiments;

FIG. 11 shows a partial cross section view of an inhaler device,according to some embodiments;

FIG. 12 is a schematic illustration of components of a mechanicallyoperated flow control system, for example as incorporated within aninhaler device, according to some embodiments;

FIGS. 13A-13D schematically illustrate a valve apparatus comprising anouter tube having valve apertures, rotatable with respect to conduitapertures, of an internal tube, for a performing a sequence of conduitopenings and closures, according to some embodiments;

FIG. 14 is a schematic illustration of another mechanically operatedflow control system, according to some embodiments; and

FIG. 15 schematically illustrates an inhaler for simultaneousadministration of substances from a plurality of chambers in acorresponding plurality of carrier airflow conduit tracts, according tosome embodiments.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present disclosure, in some embodiments thereof, relates topulmonary delivery of a drug substance using a personal inhaler deviceand, more particularly, but not exclusively, to controlling flow throughan inhaler.

In some embodiments, control of flow through the inhaler comprisesdynamic control over the flow of ambient air. In some embodiments, anamount of drug substance that is delivered to the patient from a drugdose is controlled.

Overview

A broad aspect of some embodiments relates to controlled pulmonarydelivery of one or more active substances of a drug dose to a user. Insome embodiments, delivery is performed via a personal inhaler device.

An aspect of some embodiments relates to controlling conditions ofairflow and/or temperature around, in and/or through a drug dose toachieve a targeted profile of release of a drug substance from the drugdose. In some embodiments, a targeted profile comprises a targettemperature, range of temperatures, and/or time-evolving temperature orrange of temperatures which the drug dose is heated to. Optionally atargeting profile comprises heating effected intermittently.Additionally or alternatively, a targeted profile comprises a targetedprofile of flow, for example as described hereinbelow. In someembodiments, a targeted profile comprises a function, lookup table, orother description indexing flow and temperature characteristicstogether. For example, in some embodiments, as airflow increases, moreof the heat delivered to a drug dose for drug substance vaporization ispotentially drawn away. Optionally, a targeted profile of release (forexample to achieve a particular rate of release) specifies that as anairflow increases, so does a delivery of heat. A potential advantage ofthis is to allow a more concentrated release of drug substance, whilepreventing overheating which could cause damage to the device, the drugsubstance, and/or injury to the user.

In some embodiments, a longer release time is targeted. Optionally,heating is maintained to a level which keeps a temperature of the drugdose just above a minimum effective vaporizing temperature, for example,within 1° C., within 2° C., within 5° C., within 10° C., or withinanother higher, lower or intermediate temperature above a minimumeffective vaporizing temperature. Effective vaporizing is at a rate, forexample, of 10% of the total dose substance per second, 20%/s, 30%/s,50%/s, or another higher, lower, or intermediate Lower airflow isadjusted for by lowering the heating. In some embodiments, heating andflow rate control are adjusted to compensate for limits in the range ofcontrol that each other allows. For example, as heating control reachesa limit of available power, flow is increasingly restricted, to preventover-cooling of the drug dose. Additionally or alternatively, limits tothe level of flow (for example, a minimum flow to ensure good transferof drug substance to the user) are set, and the delivery of heat isregulated.

In some embodiments, a release profile is matched in terms ofoperational parameters. For example, a release profile which targetsreleasing all of a drug substance of a drug dose over a period of 2seconds is defined in terms of operational parameters which heat thedrug and/or control flow so that the 2 second release time target ismatched. The operations parameters are determined, for example,empirically, and/or by use of models comprising known characteristics ofthe drug substance and/or the drug dose.

In some embodiments one or the other of the control possibilities isused dominantly for control of a target profile of release. For example,carrier flow is left substantially unregulated, while heating is variedto maintain a target temperature. Alternatively, heating issubstantially constant, while carrier flow is regulated to produce aneven (or other targeted) flow.

An aspect of some embodiments relates to controlling heating of a drugdose according to a sensed temperature indication and a targetedprofile. In some embodiments, temperature is measured by, for example,an infrared sensor, and/or by a contact thermal sensor. Optionally, thetemperature indication is calibrated to a temperature in degrees.Additionally or alternatively, the temperature indication is usedoperationally to set a particular level of heating. It is a potentialadvantage to control temperature based on sensed feedback, to helpensure that a targeted profile of drug substance release is met.

An aspect of some embodiments relates to controlling carrier gas flow(for example, airflow; also referred to as “carrier airflow” herein)through or adjacent a drug dose according to a determined profile, byproviding shunting airflow based on a difference between an estimatedflow through the drug dose, and the targeted profile of flow through thedrug dose. In some embodiments, a volumetric flow rate through the drugdose is measured or estimated, for example using one or more sensors;and a flow of a gas (optionally, flow of ambient air), is dynamicallymodified based on the indication from the sensor(s). In someembodiments, when flow of shunting air into the inhaler device isprevented, the flow rate through the drug dose is equivalent to aninhalation flow rate of the user. It should be understood that thecontrol of flow rate is optionally co-regulated with temperaturecontrol, for example as described hereinabove.

In some embodiments, an inhalation flow rate of the user is estimated inaccordance with an indication provided by the one or more sensors.Optionally, the indication from the one or more sensors is combined witha current opening status of one or more valves that control the flowinto and/or out of and/or within the inhaler device.

In some embodiments, for example, where natural fluctuations in theinhalation flow rate of a user occur potentially over a use session,airflow control includes dynamically modifying the flow of shuntingairflow and/or shunting airflow relative to carrier airflow. This allowssupplying the user with a flow rate at least partially governed by theact of inhalation (for example, not oversupplied with respect to a rateof inhalation), while maintaining the flow rate through the drug dose atan essentially fixed rate and/or within a specific profile.

In some embodiments, dynamic modifying of flow is effected to achieveand/or maintain a target profile of flow through the drug dose.Optionally, a target profile comprises or consists of maintaining theflow through the drug dose at a constant rate; for example, 0.5 L/min, 1L/min, 4 L/min, or an intermediate, higher or lower rate of flow.Optionally, the profile of flow through the drug dose comprises avarying flow profile, for example including a linearly increasing rate,linearly decreasing rate and/or any other profile.

The term “target profile” as used herein means a pattern of features ofairflow through an inhaler device, including one or more of: a rate offlow, a period of flow, and a distribution of flow between differentconduits and/or different tracts of the device. A target profileoptionally includes a plurality of target profiles, and optionally thetiming, duration, and/or a degree of overlap between such targetprofiles. For example: a device having a plurality of conduits, at leastone of which provides passage through a drug dose, optionally has atarget profile including a period during which at least one (sub-)target profile is imposed on flow through the drug dose and at least oneother (sub-) target profile is defined by a degree of drag, obstruction,and/or flow resistance imposed on inhalation flow drawn by a userthrough the device.

Optionally a target flow profile through the drug dose is selected tocontrol an amount of drug substance released, control timing of drugsubstance delivery, to set an inhalation depth, to target a location fordrug delivery within the body of the user, and/or control a profile ofactive substances released from the drug dose (for example by selectinga flow profile that will initially release a first drug substance andonly at a later stage of inhalation release a second drug substance). Insome embodiments, more than one drug dose substrate is contained withina drug dose cartridge of the inhaler device. Optionally, release of oneor more drug substances is controlled in accordance with a size (e.g.molecular size), weight, or another chemical or physical property of adrug substance.

In some embodiments, commencement of inhalation is detected, for examplewhen the measured inhalation flow rate is above a predefined threshold.Optionally, this threshold is a flow rate through the drug dose which isequal to the value that is to be maintained for at least part of atarget flow pattern. In some embodiments this is a value that is to bemaintained (constantly or intermittently) for at least 0.25 or even 0.5seconds. In some embodiments this rate is 0.5 L/min, 1 L/min or even 2L/min, or an intermediate rate of flow.

Optionally, commencement of inhalation triggers activation of drugsubstance release. In some embodiments, drug substance release involvesprocessing of the drug dose, for example by heating the drug dose toextract one or more active substances. In some embodiments, the drugdose comprises plant material, for example cannabis and/or tobacco, andan active substance (e.g. THC and/or nicotine) is extracted by heatingthe plant matter. Other examples for plant material include one or moreof Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia spp.,Amanita muscaria, Yage, Atropa belladonna, Areca catechu, Brugmansiaspp., Brunfelsia latifolia, Desmanthus illinoensis, Banisteriopsiscaapi, Trichocereus spp., Theobroma cacao, Capsicum spp., Cestrum spp.,Erythroxylum coca, Solenostemon scutellarioides, Arundo donax, Coffeaarabica, Datura spp., Desfontainia spp., Diplopterys cabrerana, Ephedrasinica, Claviceps purpurea, Paullinia cupana, Argyreia nervosa,Hyoscyamus niger, Tabernanthe iboga, Lagochilus inebriens, Justiciapectoralis, Sceletium tortuosum, Piper methysticum, Catha edulis,Mitragyna speciosa, Leonotis leonurus, Nymphaea spp., Nelumbo spp.,Sophora secundiflora, Mucuna pruriens, Mandragora officinarum, Mimosatenuiflora, Ipomoea violacea, Psilocybe spp., Panaeolus spp., Myristicafragrans, Turbina corymbosa, Passiflora incarnata, Lophophorawilliamsii, Phalaris spp., Duboisia hopwoodii, Papaver somniferum,Psychotria viridis, spp., Salvia divinorum, Combretum quadrangulare,Trichocereus pachanoi, Heimia salicifolia, Stipa robusta, Solandra spp.,Hypericum perforatum, Tabernaemontana spp., Camellia sinensis, Nicotianatabacum, Nicotiana rustica, Virola theidora, Voacanga africana, Lactucavirosa, Artemisia absinthium, Ilex paraguariensis, Anadenanthera spp.,Corynanthe yohimbe, Calea zacatechichi, Coffea spp. (Rubiaceae),Sapindaceae spp., Camellia spp., Malvaceae spp., Aquifoliaceae spp.,Hoodia spp. Chamomilla recutita, Passiflora incarnate, Camelliasinensis, Mentha piperita, Mentha spicata, Rubus idaeus, Eucalyptusglobulus, Lavandula officinalis, Thymus vulgaris, Melissa officinalis,Tobacco, Aloe Vera, Angelica, Anise, Ayahuasca (Banisteriopsis caapi),Barberry, Black Horehound, Blue Lotus, Burdock, Camomille/Chamomile,Caraway, Cat's Claw, Clove, Comfrey, Corn Silk, Couch Grass, Damiana,Damiana, Dandelion, Ephedra, Eucalyptus, Evening Primrose, Fennel,Feverfew, Fringe Tree, Garlic, Ginger, Ginkgo, Ginseng, Goldenrod,Goldenseal, Gotu Kola, Green Tea, Guarana, Hawthorn, Hops, Horsetail,Hyssop, Kola Nut, Kratom, Lavender, Lemon Balm, Licorice, Lion's Tail(Wild Dagga), Maca Root, Marshmallow, Meadowsweet, Milk Thistle,Motherwort, Passion Flower, Passionflower, Peppermint, Prickly Poppy,Purslane, Raspberry Leaf, Red Poppy, Sage, Saw Palmetto, SidaCordifolia, Sinicuichi (Mayan Sun Opener), Spearmint, Sweet Flag, SyrianRue (Peganum harmala), Thyme, Turmeric, Valerian, Wild Yam, Wormwood,Yarrow, Yerba Mate, and/or Yohimbe. The dosing botanical substanceoptionally includes any combination of plant material from this list,and/or other plant material. Optionally, the drug dose comprises one ormore synthetic or extracted drugs added to or applied on carriermaterial, wherein the added drug and/or the drug dose may be in the formof or comprise solid material, gel, powder, encapsulated liquid,granulated particles, and/or other forms. In some embodiments, the drugdose comprises plant material having one or more synthetic or extracteddrugs added thereto or applied thereon.

In some embodiments, a structure of the personal inhaler device includesone or more first conduits within which air entering the inhaler deviceflows through the drug dose; at least one second, shunting conduit inpneumatic communication with the first drug conduit, through whichshunting airflow (which avoids the drug dose itself) may be allowed tojoin the flow that had already passed through the drug dose; optionallya third, bypass conduit through which ambient air (e.g. a flow notcarrying a drug substance) may be allowed to flow directly to the user;and a regulating mechanism for controlling flow through the one or moreconduits, for example comprising one or more valves. Optionally, airflows into the first conduit in response to pressure reduction producedin the device during inhalation. In some embodiments, the firstconduit(s) together with the second, and/or third conduit(s) join toproduce a combined flow. Optionally, two or more of the conduits unitein proximity to and/or within the mouthpiece of the inhaler device. Itis to be understood that an “at least one first conduit” (or second orthird conduit, and/or drug, shunting, or bypass conduit) is alsoequivalently referred to herein as “a first” (or other) “conduitcomprising at least one tract”. Thus, for example, a single conduit forone of the drug substance-bearing, shunting, or bypass airflow functionsis optionally comprised of two, three, or more tracts.

In some embodiments, at least one flow rate sensor is positioned withinthe device, at a location suitable to detect a rate of flow that passedthrough the drug dose, for example being positioned within the drugconduit distally to a connection between the shunting conduit and thedrug conduit. In some embodiments, input from the sensor is received ona controller of the inhaler device, which in turn operates the one ormore valves accordingly. In an example of operation of the device: ifthe target flow rate through the drug dose comprises a constant rate of1 L/min, and the sensor detects a flow rate of 3 L/min through the drugdose, the controller will open at least one shunting conduit to allowambient flow at a rate of 2 L/min into the drug conduit, therebyreducing the upcoming flow rate through the drug dose to the target 1L/min, while still providing the user with a rate of 3 L/min, similar tothe inhaled rate. A valve which operates to control a flow rate througha drug carrier conduit by a relative opening or closing which controls aflow rate in a shunt conduit is termed a “shunt valve” herein. A shuntvalve is optionally located within a shunt conduit; additionally oralternatively, it is located in a drug conduit.

An aspect of some embodiments relates to a sequence of flowmanipulations through an inhaler device, which provides a perceptibleindication to a user. In some embodiments, the sequence of flowmanipulations comprises a significant reduction in the flow through thedevice, optionally to a full obstruction, which is optionally followedby allowing resumed flow. Optionally allowing resumed flow includesallowing a rapid flow, being significantly faster than before thereduction.

In some embodiments, the partial obstruction of flow includesobstructing all flow through the device other than flow through drugdose, to flush residual released drug substance into and/or from theconduit. Optionally, the partial obstruction of flow includes a fullobstruction (or almost full), in which all conduits are blocked tosignificantly reduce pressure in the conduits, enough to be sensed bythe user. Potentially, by attempting to inhale against partial or fullobstruction, a user naturally increases inhalation effort, creatingincreasingly negative pressure within the device. Optionally, thepartial obstruction is followed or replaced by the full or almost fullobstruction.

In some embodiments, a rapid pulse of flow is allowed by opening atleast the bypass (third) conduit, to allow ambient airflow directly tothe user. Additionally or alternatively, the drug conduit and/or theshunting conduit are opened as well. In some embodiments, when rapidflow is allowed, drag forces are reduced, reducing a resistanceencountered by the user when inhaling through the device. Optionally,reduction of drag forces is obtained by allowing the rapid flow throughan opening having a cross sectional area substantially larger than thecross sectional area through which drug substance infused flow wasprovided. In some embodiments, the pulse of flow includes a total volumewhich is about equal to or even larger than an anatomic dead space ofthe user, for example 150 ml or larger, chasing the drug substancedeeper into the lungs, potentially ensuring deep lung delivery, and/orreducing the amount of drug substance exhaled immediately after usingthe inhaler.

An aspect of this disclosure relates to producing circumferentialairflow when delivering a drug substance through a conduit, in whichflow comprising a higher drug substance concentration is surrounded byflow comprising a lower drug substance concentration. This may be seenas a “sleeve-like” effect of laminar flow wherein the circumferentialairflow flows around air that passed through the drug dose with littlemixing, thereby reducing contact of released drug substances withconduit walls. In some embodiments the sleeve-like effect is obtained byallowing entry of shunting flow, for example through the shuntingconduit(s), into the first conduit to join carrier airflow that hasalready passed through the drug dose. For example, the flow through theshunting conduit(s) is provided through a plurality of openingssurrounding the conduit. Optionally, this is performed uniformly aroundthe central flow, to reduce turbulence in the combined flow. In someembodiments, flow rate is controlled to keep flow in a laminar(substantially non-turbulent) flow regime, at least near the conduitwalls. For example, flow velocity leading to a Reynolds number of 2100or less is maintained. However, it is to be understood that the criticalReynolds number below which flow maintains laminar characteristicsvaries according to the particular geometry of the conduit.

In some embodiments, a double sleeve-like effect is obtained by allowingmore ambient flow at positions more proximal than the aforementioned.This may be performed, for example, by having two or more sets of tractsof the shunting conduit(s) which provide ambient air sequentially alongthe flow path. Additionally or alternatively, a double sleeve-likeeffect is obtained by opening the bypass conduit(s) so that at least ata proximal portion of the mouthpiece all flow is united, while the airwith the highest drug substance concentration flows through asubstantially center of the conduit.

A potential advantage of a sleeve-like effect may include reducingadherence of drug dose residues and/or active substances to the walls ofthe conduit, which may be especially advantageous when the drug dosecomprises oily materials, for example comprising plant material such ascannabis.

An aspect of some embodiments is the control of an inhaler device toproduce changes in a flow profile (for example, a flow profile whichadjustably regulates flow through a plurality of conduits) by themovement of a mechanism which provides control over two or more valvesat once. In some embodiments, the mechanism comprises at least twoapertured elements, for example, at least two disks or at least twocylinders. Movement (for example, rotation and/or straight linetranslation) of one apertured element relative to the other elementchanges the relative alignment of the apertures. Optionally, aperturesare arranged so that a plurality of valves (for example, valves to acarrier conduit) are opened and closed together by a single movement.Optionally, apertures are arranged so that at least one valve openswhile another valve closes. Optionally, apertures are arranged so thatvalve opening and closing can be performed relatively separately amongtwo or more valves, depending on the motion and/or relative position ofthe valve members.

As used herein, the term “ambient air” includes air entering a conduitof the device. Ambient air optionally comprises room air or anymodification thereof, such as addition of one or more drug substances tothe air, humidification of the air, and/or other modifications.Optionally, ambient air relates to air that flows to the user via aconduit without passing along or via the drug dose.

Herein, the term “proximal” is used in reference to a portion, componentand/or opening of the inhaler device in relative proximity to the userend during an inhalation event, e.g. a mouthpiece. A component may bephysically “distal” or “proximal”, and/or it may be at a position thatis relatively more distal or proximal than another position. Forexample, the term “distal” is used in reference to a portion, componentand/or opening of an inhaler device which is closer to an end of thedevice opposite the user end. Optionally, a component is described asfunctionally or operationally “distal” or “proximal”. For example“distal” could be used in reference to a conduit opening through whichair initially enters the device, before advancing through the path offlow to the user, regardless of the physical position of the openingwith respect to the user end.

As used herein, the term “drug substance” or “active substance” is usedin reference to one or more pharmaceutically or otherwise activesubstances, for example therapeutic or medicinal substances and/orsubstances for recreational use, and/or substances for testing. In someembodiments an “active” substance is such substance which may have aneffect on a user's body or any part thereof. A “drug substance” may beadministered to a user, for example by vaporization, suspension, and/orvolatilization of the drug substance into gas (typically air) inspiredby a user. Optionally, a drug substance includes one or more non-activematerials accompanying the active portion of the drug substance.

The term “drug dose” denotes material, arranged for use in an inhalerdevice, from which one or more drug substances are released (e.g.extracted or vaporized). In some embodiments the material comprises theone or more drug substances. A drug dose is optionally arranged, forexample, as a pallet of the drug dose material. The terms “drugcartridge” and “drug repository” include structures that are configuredfor the handling and/or structure maintenance of a drug dose (forexample, for supporting a drug dose pallet), including, for example, oneor more of: a carrier, housing, frame, packaging, or other structureassociated with the drug dose material itself; this is also referred toas a “dose unit” or “drug dose unit”. Optionally, the drug dose togetherwith all additional structures is configured to permit airflow throughthe drug dose at least at a rate of 0.5 L/min, 1 L/min, 4 L/min, or anintermediate, higher or lower rate of flow.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth in the following description and/orillustrated in the drawings. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

Reference is now made to FIGS. 1A-1B, which are schematic flowcharts ofgeneral (FIG. 1A) and detailed (FIG. 1B) methods for pulmonary deliveryof one or more drug substances to a user using an inhaler device,according to some embodiments of the invention.

FIG. 1A is a general method of controlling flow through an inhalerdevice. In some embodiments, as further detailed below, a target profileof air flow through the drug dose is optionally selected (block 120). Insome embodiments, selecting the target profile comprises selecting oneor more parameters such as flow rate, total volume, duration, flowvelocity, and/or other parameters of the flow that passes through thedrug dose and/or through one or more conduits of an inhaler device. Insome embodiments, a target profile is selected prior to providing thedrug substance to the user through the inhaler device (for example,during manufacturing of the device, and/or during a previousconfiguration of the device). Additionally or alternatively, the profileis selected and/or modified during a use session, for example during aninhalation of the user through the inhaler device. Additionally oralternatively, the profile is selected before a new use (e.g. use by adifferent user and/or for a different drug substance or different drugsubstance concentration). Optionally, the profile is determined in theprocess of design or manufacture of the device, such that the device canoperate only according to the predefined profile without necessarilyperforming an act of selection during use.

In some embodiments, to maintain flow (e.g., carrier airflow) throughthe drug dose at the target profile, shunting air flow into the deviceis dynamically controlled according to an estimated flow through thedrug dose and the target flow profile through the drug dose (block 122).In some embodiments, shunting air flow unites with flow that had alreadypassed through the drug dose. In some embodiments, shunting flow isallowed into the inhaler device (for example by opening a valve) inresponse to a difference between the estimated flow through the drugdose, and the target flow profile through the drug dose.

The following method, for example as described in FIG. 1B, is optionallyused for inhalation of pharmaceuticals or any other drug substancesusing a personally operated inhaler device. In some embodiments, aninhaler device suitable for implementation of a method, for example asdescribed herein, comprises at least a first conduit through which oneor more active substances are delivered to the user (the first conduitwill be hereinafter referred to as “drug conduit”). This drug conduitpasses through a drug repository where the drug substance or one or moreactive substances are added to air flowing through the repository; asecond conduit that joins the drug conduit at a more proximal locationalong the drug conduit, in which air has already flown past the drugrepository, allowing ambient air to enter and join the drugsubstance-infused air that passed via the repository, thereby increasinga volume of the air flowing through the drug conduit (the second conduitwill be hereinafter referred to as “shunting conduit”); optionally athird conduit conducting ambient air directly to the user (the thirdconduit will be hereinafter referred to as a “bypass conduit”); and oneor more regulating means (for example valves), for controlling flow intothe inhaler device, flow through the conduits and/or in between theconduits, and/or flow out of the inhaler device.

In some embodiments, the drug conduit and the bypass conduit lead theflow to a common passage, for example a passage through the mouthpiece.In some embodiments, the method comprises detecting a flow rate througha drug repository. In some cases, for example when entry of flow intoconduits other than the drug conduit(s) is prevented, flow rate throughthe drug dose (also termed drug repository) is indicative to theinhalation flow rate of a user (block 100). In some embodiments, flowrate is detected by one or more sensors, for example a differentialpressure sensor. Additionally or alternatively, flow rate is sensedand/or adjusted mechanically, for example using pressure release valves,duck billed valves, and/or the like.

In some embodiments, commencement of inhalation is detected, for exampleby measuring a flow rate that is above a defined threshold. In someembodiments, a flow rate is measured continuously during inhalation.Alternatively, a flow rate is measured occasionally or periodicallyduring inhalation; for example: every 10 msec, every 50 msec, every 100msec, every 500 msec, every second, or over intermediate, longer orshorter time periods. In some embodiments, flow rate measurement isperformed within the drug conduit, at a location distal to a junctionbetween a shunting conduit and a drug conduit.

In some embodiments, drug substance release is activated (block 102).Optionally, commencement of inhalation triggers activation (e.g. when asensed flow rate is significantly greater than zero). In someembodiments, drug substance release is activated only when air flowthrough the drug dose is sensed to be above a higher threshold.Optionally this threshold equals a flow rate through the drug dose thatis maintained constant for at least a portion of an inhalation event. Insome embodiments, this threshold is 1 L/min, 0.5 L/min, 2 L/min, or anintermediate, higher or lower flow rate. In some embodiments drugsubstance release is activated additionally or alternatively subject tobeing prompted by a user, for example by pressing a button or shiftingthe inhaler device to a ready-to-use position.

In some embodiments, activation of drug substance release comprisesevacuating one or more active substances of the drug dose. Optionally,evacuation comprises one or more of heating, vaporizing, initiating achemical reaction, changing a physical state of the drug dose material(e.g. turning to aerosol), simply allowing air to flow through the drugrepository and carry the drug substance, and/or other methods suitablefor releasing and/or extracting the drug substance to deliver it to theuser. Optionally, drug substance release is activated for a defined timeperiod. Alternatively, drug substance release is activated for a timeperiod which is dynamically adjusted, for example based on the flow ratemeasurement.

In some embodiments, air entering the inhaler in response to suctionproduced in the device during inhalation flows through the drug conduit,passing the drug repository (block 104). Optionally, all other conduitsare obstructed at this stage.

In some embodiments, a target flow profile through the drug repositoryis maintained by regulating flow of ambient air (block 106), such as airentering through the shunting conduit. In some embodiments, flow ofambient air is regulated based on differences between the current flowrate through the drug dose, as detected for example by the pressuresensor, and the target flow rate through the drug dose.

In some embodiments, a target flow profile through the drug dosecomprises or consists of a constant flow rate, for example 1 L/min, 0.5L/min, 2 L/min, or an intermediate, higher or lower flow rate,optionally for a certain period of time. Additionally or alternatively,a target flow profile comprises an increasing or decreasing flow rate.Optionally, the change in flow rate is monotonic. Optionally, the changein flow rate is linear. Additionally or alternatively, a target flowprofile comprises other profiles, such as one or more of constant flowthrough the drug dose followed by unregulated flow through the drug dose(optionally with all other conduits closed); constant flow through thedrug dose followed by allowing of rapid flow through the bypassconduit(s); constant flow through the drug dose followed by a partial orfull obstruction of the conduits, and/or other profiles or combinationsthereof and any other flow profile described herein.

In some embodiments, the target flow profile is set in accordance withone or more of the following parameters: the type of drug dose and/orsubstance, the amount of drug dose and/or substance, the time periodrequired to release the drug substance, the type of processing of thedrug dose (e.g. heating), and/or user parameters. For example, for auser (e.g. a small child) that cannot inhale more than 500 ml/min, flowthrough the drug dose may be adjusted to a set maximal and/or constantvalue of 500 ml/min. In another example, a user suffers from shortnessof breath, and though capable of inhaling a volume of, for example, 2L/min, this is but for a limited time period, such as 2 seconds.Optionally, then, a rate of flow through the drug dose is set to ahigher value, for example 1.5 L/min. This higher value may be set inorder to deliver in the 2 second time period an amount of drug substancenearing that which would have been provided over, for example, a 3second time period to a user capable of longer inhalation. Optionally,release of the one or more drug substances is accelerated, for exampleby modifying a heating profile. In some embodiments, a target flowprofile through the drug dose contributes to quantifying and/or timingdrug substance release.

In some embodiments, a target profile of flow through the drug dose isselected to increase control over the dosage of drug substance inhaledby the user. For example, if a strong suction force is produced in thedevice during inhalation, air flow at a relatively high velocity willenter the device and pass through the drug dose, possibly increasing theamount of drug substance released over a target amount. In an embodimentin which the drug dose is heated, flow at a higher velocity than thetarget may cause premature cooling of the drug dose. Therefore, bycontrolling a rate of airflow through a drug dose, the amount of drugsubstance inhaled from a dose unit having a given composition may beessentially the same for a wide range of users.

In some embodiments, regulating of ambient air flow comprises allowingflow through the shunting conduit(s) (e.g. by opening a valve to allowflow between the drug conduit and the shunting conduit and/or bycontrolling the extent to which it is opened) based on the measuredinhalation flow rate. In some embodiments, a threshold for opening theshunting conduit comprises a detected inhalation flow rate that ishigher by at least 1%, at least 5%, at least 20% or an intermediate,higher or lower percentage higher than an initial target rate of flowthrough the drug dose, such as a rate of 1 L/min.

In an example, if the target flow profile through the drug dose is setto a constant 1 L/min, and the user's initial inhalation flow rate ismeasured at 3 L/min (as sensed within the drug conduit, assuming otherconduits are initially closed), the shunting conduit will open and allowair to enter at a flow rate of 2 L/min. The target constant profile willthen be maintained by detecting a deviation in flow rate through thedrug conduit (at a distal portion of the conduit, before the joining theshunting conduit) from 1 L/min, and dynamically regulating ambient flowthrough shunting conduit accordingly. Assuming natural fluctuations inthe inhalation flow rate of the user, the “completing” ambient flow ratethat is allowed into the device will vary at various time points duringinhalation. In such cases, the sensed flow rate would be approximatelyequal to the difference between the user's inhalation flow rate and theflow rate through the shunting conduit. For example, if in the abovecase the user's inhalation increased to 3.5 L/min, and the flow rate viathe shunting conduits was set to 2 L/min, then a flow rate of about 1.5L/min would be sensed. In such case the shunting conduit will openfurther to allow air to enter at a flow rate of 2.5 L/min, therebyreducing the sensed flow rate back to about 1 L/min. Likewise, if theinhalation flow rate is reduced (e.g. to 2.5 L/min.) the shuntingconduit will partially close so that air may enter at a flow rate of 1.5L/min only.

A potential advantage of dynamic regulation of ambient flow based on thecurrent rate of flow or estimation thereof and the target flow profilethrough the drug dose includes providing a user with total volume ofambient air mixed with drug substance-infused air which is equal to thevolume inhaled by the user, thereby allowing different users to breathedifferently through the inhaler without significantly affecting air flowvia the drug repository, and consequently the amount of inhaled drugsubstance.

In some embodiments, if a measured flow rate through the drug dose whichis indicative of the inhalation flow rate or a measured inhalation flowrate is lower than a threshold, for example being lower than the targetflow rate required through the drug dose, such as less than 1 L/min inthe example described above, drug substance release will not beactivated. Optionally, the inhaler device will provide an indication tothe user (e.g. by a light indication, sound indication, tactileindication, and/or other indication) to increase air intake duringinhalation. If this is sensed at a later time during operation drugsubstance release may be terminated, for example if the flow falls belowthe threshold for at least a specific period of time.

Additionally or alternatively, a fan, a blower and/or other air pressuresource is used with the inhaler to supply additional flow into theinhaler. This configuration might be specifically advantageous in aninhaler device used by weak users, elderly users, young children, and/orother users incapable of inhaling at a minimal flow rate for drugsubstance release. Optionally, the fan or blower is operable in reverse.Potentially this mimics the effect of a closed or partially closedvalve, acting to increase apparent resistance to air flow through aconduit.

In some embodiments, drug substance is released over a selected timeperiod. In some embodiments, the time period is a target time period,for example a constant time period, such as 3 seconds, 5 seconds, 1.5seconds, or intermediate, longer or shorter time periods. In someembodiments, a time period for drug substance release (e.g. by heatingthe drug dose) is dynamically modified or determined during inhalation,for example based on the detected inhalation flow rate. In an example,if the inhalation flow rate of the user is slightly under a target flowrate required through the drug dose (for example 5%, 10%, or 20%smaller), the time period of drug substance release is lengthened,and/or the heating profile is adjusted, to compensate for the lower flowrate; for example, lengthened from 3 seconds to 3.5 seconds.

In some embodiments, optionally at the end of drug substance release orshortly thereafter, all flow other than flow through the drug conduit isobstructed (partially or completely), to flush the remaining drugsubstance and deliver it to the user (block 108). Optionally, flowthrough the shunting conduit is gradually restricted before optionallybeing fully obstructed, to increase flow through the drug dose. It isnoted that flushing of the drug substance may also take place when otherconduits are open, albeit possibly at a slower rate.

In some embodiments, flow to the user is partially or fully obstructed(block 110). In some embodiments, the blocking occurs at the terminationof the inhalation (for example, the events described in relation toblock 112 are skipped). In some embodiments, the obstruction durationand/or degree is predefined. Alternatively, the obstruction durationand/or degree is set dynamically, for example determined according to ameasured flow rate and/or a measured negative pressure buildup in thedevice during the obstruction period. Optionally, the target duration ofobstruction is, for example, according to the user's sensed inhalationflow rate, to be long enough to reduce the internal pressure within thedevice, optionally generating a vacuum strong enough to be sensed by theuser and/or to produce a consequent rapid flow or volume (for example avolume larger than an anatomical dead space, such as 150 ml or larger)upon release of the obstruction. In some embodiments, an obstructionduration set for a user inhaling at a relatively high flow rate will beshorter than an obstruction duration set for a user inhaling at arelatively low flow rate. Potentially, the short duration obstruction inthe higher flow rate user will be sufficient for generating suctionstrong enough to be sensed by the user, while the low flow rate usermight need a longer time period to sense the suction.

At block 112, in some embodiments, flow is allowed through the deviceand to the user, optionally at a relatively high rate. This isoptionally after obstruction such as described in relation to blocks 108and/or 110. Alternatively, the resumed flow is allowed without a priorperiod of flow restriction. Optionally, the rate of the resumed flow ishigh enough to admit a relatively large volume of air to cause the drugsubstance inhaled before the obstruction to advance deeper into thelungs of the user. Optionally, at least the bypass conduit is opened(for example, by opening of a bypass valve, optionally under the controlof a bypass valve controller) to allow general ambient air flow to theuser without being restricted by the drag of the drug conduit. In someembodiments, the drug conduit and/or shunting conduit are opened aswell. In some embodiments, the duration of the advancing phase of themethod is limited by the lung capacity of the user. Optionally, theopening of pathways for the advancing is for a limited period of time,for example, less than 4 seconds, 3 seconds, 2 seconds, 1 second, orless than another greater, lesser, or intermediate period. Optionally,at least one of the first conduit, the second conduit and the thirdconduit are left open for a period of time that extends beyond the endof an inhalation session. In such case, the conduit(s) may close inresponse to an action taken by the user (e.g. shifting the inhalerdevice to a “closed” position and/or pressing or releasing a buttonand/or when a device is primed for a later inhalation event or when anew inhalation is sensed).

Optionally, opening the bypass conduit effectively increases a crosssection (and/or lowers a flow resistance) of the mouthpiece relative tothe effective cross section (and/or flow resistance) that exists whenonly the drug conduit and/or shunting conduit are open. The effectivecross section may be taken to mean a cross section that defines the dragforces resisting the flow of air to the user. For example, the effectivecross section may be taken to mean a minimal cross section through whichthe flow passes to the user. For example, this effective cross sectionmay be the sum of the minimal cross sections of all conduits throughwhich air flows at a given point. Optionally, the cross-sectional areaof the bypass conduit is at least 25% larger than the cross-sectionalarea of the drug conduit, at least 50% larger, at least 100% larger, atleast 200% larger, or larger by another greater, smaller, orintermediate factor.

Optionally, drag forces resisting flow to the user are reduced by theenlargement of effective cross section through the mouthpiece, allowingflow of higher velocity to the user at the same applied suction power.Optionally, the user senses a sudden decrease in resistance whenbreathing through the inhaler as compared to the relatively restrictedbreathing during drug substance release and/or during the obstructionperiod.

It is noted that in some embodiments, a full obstruction of flowoptionally does not take place, and the bypass conduit is opened toallow ambient flow to the user to provide the large enough air pulse.

In some embodiments, an indication regarding the use state, for exampleregarding the inhalation state is provided to the user (block 114).Optionally, the indication is provided to indicate that a use session iscompleted, and the user may stop inhaling through the device. Theindication optionally comprises, for example, a tone, vibration, and/orlight. In some embodiments, the indication comprises direct lung-inhalerdevice feedback obtained during use. For example, a specific pattern ofinhalation that is elicited from the user by the inhaler may be includedin such indication. More particularly, the indication may include thesequence of actions including, for example, allowing flow during drugsubstance delivery, followed by a substantial reduction in flow,optionally to a full obstruction. Optionally the sequence includes afollowing resumed pulse of air, optionally at a higher velocity and/orreduced resistance relative to one or all the preceding flow periods inthe sequence. In another example, the indication includes preventing airflow via the device at the end of the session, such that the highresistance is sensed by the user as an ending point. In someembodiments, a particular sequence of flow resistances experienced bythe user indicates successful inhalation (for example, controlledflow/restricted flow/free flow), and any other pattern indicates aproblem has occurs. In some embodiments, one or more distinct “warningpatterns” are defined; for example, a fluttering pattern, a full flowstop pattern, or another pattern of modulated flow resistances.Optionally, an indication provided to a user by a pattern of flowresistances is combined with additional audio, visual and/or tactileindication. Potentially, this provides a more conventional indication tothe user that, for example, clarifies the indication of the pattern.

In some embodiments, a “substantial reduction in flow” or “significantreduction in flow” means a reduction of the “rate of total airflow” toan inhaling user through the device. This “total airflow” relates to allflow of air through the device to the inhaling user, through allconduits, for example, a total volume flowing within a period ofseconds, milliseconds, a single inhalation, or another period. Herein,“rate of airflow” is a material flow rate of gas (usually, but not only,derived from ambient air), for example, a volumetric flow rate of air. A“substantial reduction” in the rate of total airflow optionally includesany reduction that is sensed by an inhaling user and may include areduction of, for example, airflow rate of 50% or more or even 75% ormore or even complete or near complete obstruction with a reduction ofat least 95% or even 100% in the rate of total airflow.

In some embodiments, the indication includes allowing flow during drugsubstance delivery under some resistance (e.g. drag on total airflow),followed by a release or significant reduction of the resistance (e.g.by opening a valve that allows bypass airflow that does not pass througha drag imposing constriction).

In some embodiments, the flow rate through a device after obstruction isremoved or reduced is at least 25%-50% of the flow rate beforeobstruction, or is approximately equal to the flow rate beforeobstruction. In some embodiments, the flow rate through a device afterobstruction is removed or reduced (or before the change in resistance)is at least 25% larger than before obstruction (or before the change inresistance) or 50% larger, at least 100% larger, at least 200% larger,or larger by another greater, smaller, or intermediate factor. In someembodiments, where obstruction is less than complete, the flow rateafter obstruction is removed or reduced is at least 50% larger than theallowed flow rate during obstruction, at least 100% larger, at least200% larger, or larger by another greater, smaller, or intermediatefactor.

In some embodiments a higher allowed flow rate after obstruction orresistance is removed (or reduced) may be advantageous in facilitatingfaster and/or deeper and/or a higher volume of inhalation.

Additionally or alternatively, indication to the user is provided by avisual indication (e.g. a LED indication), a tactile indication (e.g. avibration in the inhaler device), an audible indication, and/or anyother indication.

Reference is now made to FIG. 2, which is a schematic diagram ofcontrolled flow through an inhaler device, according to some embodimentsof the invention.

In some embodiments, flow throughout the inhaler device can be generallydivided into three main flow paths: a first path of flow through thedrug dose; a second optional path of ambient air flow that joins thefirst flow path; and a third optional flow path of ambient air thatflows to the user without significantly affecting flow via the firstflow path, for example by being provided directly to the user. In theschematic diagram shown herein, inhalation of user 200 produces suctionin the device, causing air to enter the device. In some embodiments,airflow 202 entering the device flows through the drug dose. The drugdose and/or drug cartridge comprising the drug dose is held in positionby a holder of the inhaler device. The holder is configured to hold thedrug dose or a drug cartridge comprising the drug dose such that atleast 90% of the carrier airflow passes through the drug dose. In someembodiments, at least 98% or even 100% of the carrier airflow passesthrough the drug dose. For example, the holder may position a dose unitwithin a tract of the drug conduit and seal airflow around the drugdose, such that only (or mostly) airflow that passes through the drugdose reaches the mouthpiece. Optionally, the sealing prevents airflowfrom contacting sensitive mechanical and/or electrical components of theinhaler. To control a rate of flow through the drug dose 202, optionallyaccording to a target profile, a flow regulator 204 is positioned todynamically govern ambient flow 206 into the inhaler device. In someembodiments, ambient air that entered the device is directed to join theflow that has already passed through the drug dose (via the second orshunting flow path). Additionally or alternatively, ambient air thatentered the device flows directly to user 200 (via the third or bypassflow path).

In some embodiments, regulation of ambient flow 206 is performed basedon a sensed flow rate which is determined at least partially by aninhalation force applied by user 200. Additionally or alternatively,regulation of ambient flow 206 is performed based on a differencebetween an actual rate of flow through the drug dose, and a target rateof flow through the drug dose. Optionally, a rate of flow through thedrug dose or an indication thereof is sensed by a sensor 208, configuredfor example distally to juncture 210 in which ambient flow 206 or partthereof joins the flow that has already passed through the drug dose. Insome embodiments, when all paths other than the drug substanceextraction flow path are obstructed, a rate of flow through the drugdose indicates the inhalation flow rate of the user. This indication maybe acquired, for example, at the beginning of a use session, to detectcommencement of inhalation, for example by measuring flow rate above acertain threshold.

In some embodiments, when the detected flow rate through the drug doseis higher than a target flow rate through the drug dose (the targetrate), flow regulator 204 permits ambient flow 206 or part thereof tojoin the flow that has already passed through the drug dose. As the usercontinues to inhale, the upcoming flow rate through the drug dose isreduced (as the flow that forms the “difference” between the target flowand the detected flow is allowed to enter through the ambient flowpath).

In some embodiments, as inhalation continues, and if ambient flow isalready allowed into the device, the sensor will detect a rate of flowthrough the drug dose, which may be different than the inhalation flowrate. Optionally, when a flow rate through the drug dose that is higheror lower than certain target is detected, the rate of ambient flow intothe device will be dynamically modified to reduce or increase theupcoming rate of flow through the drug dose to the target value.

A potential advantage of the flow control mechanism described herein mayinclude providing the user with a flow rate that is similar to theinhalation flow rate, while maintaining flow through the drug dose at atarget profile, optionally without significantly affecting the amount ofdrug substance that is inhaled by the user.

In some embodiments, flow regulator 204 permits ambient flow 206 to passto the user without affecting the flow rate through the drug dose (e.g.directly to the user), at least for a portion of a use session.Optionally, such ambient flow is provided to the user in parallel to theproviding of flow that passed through the drug dose and/or in parallelto a mixture of flow that passed through the drug dose and ambient flow.Alternatively, ambient flow without affecting the flow rate through thedrug dose is provided separately, for example when providing the userwith an air pulse to advance the drug substance into the lungs, suchtowards the end of a use session.

In some embodiments, flow regulator 204 is configured to control aprofile of the ambient flow (e.g. control one or more of a rate,velocity, pressure, volume and/or other parameters). Optionally, theflow is controlled by dynamically modifying a cross sectional area of apassage through which the ambient air enters the device and/or advanceswithin the device, such as a by valve that is shaped to allow free flowand/or partial flow and/or no flow through the passage.

In some embodiments flow regulator 204 is mechanical and reactsautonomously to perceived pressures. In such cases, in some embodiments,a flow controller separate from the regulator itself is not included inthe device.

In some embodiments, flow regulator 204 is activated by a controller212. Optionally, controller 212 is programmed to receive an indicationfrom sensor 208, such as an indication of flow rate through the drugdose, and to activate regulator 204 accordingly. In an example, sensor208 provides an indication of flow rate that is higher than a targetflow rate through the drug dose, and controller 212 activates flowregulator 204 to permit entry of ambient flow 206, such as by at leastpartially opening a valve.

In some embodiments, the inhaler device comprises one or more additionalflow sensors, such as a sensor configured within a shunting conduit todetect parameters (e.g. flow rate) of the ambient flow entering throughthe shunting conduit to join the flow in the drug conduit, a sensorconfigured within a bypass conduit to detect parameters (e.g. flow rate)of the ambient flow entering the device, a sensor configured within themouthpiece to detect parameters of flow exiting the device, optionallycollecting data of a total volume of flow provided to the user, such asduring a use session.

In some embodiments, a measure of inhalation volume, such as by the oneor more sensors of the inhaler device, can be used as an indication of aphysiological condition of the user, such as pain level. It is suggestedthat when a user is experiencing breakthrough pain, relatively highinhalation volumes may be observed. In some embodiments, an amount ofdrug substance provided to the user is modified based on the detectedinhalation, optionally in real time.

In some embodiments, controller 212 is configured for storing datareceived from the one or more sensors. In some embodiments, controller212 is configured to transmit data such as parameters of inhalation, atotal volume of flow that was provided, parameters of flow that passedthrough the drug dose, and/or other parameters which were received asinput on the controller to a user interface and/or to a physicianinterface. Optionally, the user interface is configured on a hand helddevice, such as a smart phone, smart watch/band, personal computer, andthe like. Additionally or alternatively, data is communicated to theuser through the inhaler device, for example presented on a screenmounted on an external housing of the device and/or via telemetry to aseparate device.

In an example, if the user inhales at a rate which is lower than athreshold required for activating drug substance release, the inhalationflow rate will be detected by the one or more sensors, which in turnwill signal the controller, which in turn will provide an indication tothe user to increase inhalation effort. Additionally or alternatively,the controller will operate a fan, a blower and/or other pressure sourceto supply the required flow, compensating for the low inhalation rate ofthe user. In another example if the user inhales at a rate which islower than a threshold required for activating drug substance release,the device will not activate drug substance release and a notificationmay be provided to the user.

Reference is now made to FIG. 3, which is a schematic illustration ofcomponents of a flow control system, for example as incorporated withinan inhaler device, according to some embodiments of the invention.

In some embodiments, the system comprises a conduit 300 for delivery ofone or more active substances of a drug dose. In some embodiments,conduit 300 extends from a chamber 302 attached to the conduit at aposition distal to the user, to (or optionally through) a mouthpiece 304positioned at a proximal end of the conduit. Conduit 300 ends with anopening 306 through which the drug substance exits the conduit in thedirection of a user.

In some embodiments, conduit 300 is shaped and/or sized to produce adrag force which increases a resistance to inhalation of the user. Forexample, a relatively small cross-sectional area of opening 306 ofconduit 300 increases drag. Optionally, the resistance is sensed by theuser, and might induce the user to increase inhalation efforts.

In some embodiments, chamber 302 comprises a drug repository 310. Thedrug repository is held in position within the device by a holder. Adrug dose within repository 310 may be in to the form of solid material,gel, powder, encapsulated liquid, granulated particles, and/or otherforms. Optionally, the drug dose is processed within the device beforeit is provided to the user, for example to extract one or more activesubstances, for example by heating. In some embodiments, drug repository310 includes plant material, for example cannabis and/or tobacco, fromwhich one or more active substances such as THC and/or nicotine areextracted, for example as further described herein. In some embodiments,for example when the drug dose comprises plant material, a smoke-likesubstance may be added to the flow through the device to imitate commonmethods of use or treatment such as smoking of a cigarette, a cigar, apipe or a cannabis cigarette. Optionally the device is fashioned toexternally resemble the item used in such common uses.

In some embodiments, at least one sensor 314 is positioned at a locationsuitable for assessing one or more parameters of the flow that passesthrough the drug repository 310, for example within chamber 302. In someembodiments, the sensor 314 is configured to measure one or more of:rate, pressure, velocity, volume of the flow, or another direct orindirect indication of flow rate. Optionally, the flow estimation takesinto consideration a fixed volume of the chamber. In some embodiments,the sensor is positioned at a location in which it is less prone todamage and/or less prone to any physical, chemical or mechanicalphenomena that may affect the sensor's performance. For example, in adevice in which a vaporization process takes place, the sensor may bepositioned away from fumes, which may impede sensitivity and/or shortenthe sensor's life. Optionally, sensor 314 is positioned distal to anopening 306 which is a proximal opening of conduit 300, and proximal toa drug repository 310. A potential advantage of this position is toallow sensing of pressure changes at a position where change in pressurecan be related to flow rate and/or total flow volume.

In some embodiments, chamber 302 comprises a distal opening 316 throughwhich air enters, optionally in response to suction produced byinhalation of the user. Additionally or alternatively, in someembodiments, a pressure source schematically shown as a fan 312 ispositioned at or near distal opening 316 to actively force air into thechamber. In some embodiments, a macro filter 318 extends across theopening, to reduce or prevent debris and/or other contaminating materialfrom entering the chamber. In some embodiments, fan 312 is activated(for example by a controller) in response to an indication from sensor314, such as an indication of inhalation flow rate that is lower than athreshold needed to activate drug substance release.

In some embodiments, a shunting conduit 320 joins conduit 300 at alocation which is more proximal to the user than a location in whichflow through chamber 302 passes through the drug repository. Optionally,shunting conduit 320 joins conduit 300 at a location which is close to alocation in which flow through chamber 302 passes through the drugrepository. In some embodiments, ambient flow into conduit 300 throughshunting conduit 320 is controlled by one or more valves 322 thatoptionally act as shunt valves.

In some embodiments, ambient flow entering the device is deliveredthrough a bypass conduit 324 without being restricted by drag of thedrug conduit 300. In some embodiments, ambient flow through conduit 324is controlled by one or more bypass valves 326. Optionally, theeffective cross-section (e.g. the opening) of bypass conduit 324 islarger than that of drug conduit 300 (e.g. proximal opening 306). Thecombined effective cross sections of bypass conduit 324 and drug conduit300 affect the flow rate through opening 308 of mouthpiece 304.Accordingly, the effective cross section of drug conduit 300 is forexample at least 2 times smaller, at least 3 times smaller, at least 5times smaller or intermediate, larger or smaller values. Additionally oralternatively, the summed cross-sectional area of the proximal openingsof the bypass conduit 324 and the drug conduit 300 is at least 25%larger than the proximal opening(s) of the drug conduit 300 alone, atleast 50% larger, at least 100% larger, at least 200% larger, or largerby another greater, smaller, or intermediate factor.

In an embodiment, opening 306 has a diameter of 3 mm, and the opening ofbypass conduit 324 has a diameter of 8 mm.

It is noted that entry and/or passing of flow such as ambient flow isprovided, in some embodiments, by a coupling other than a junctionbetween two or more conduits. In an example, ambient air flow to thedrug conduit and/or ambient air flow joining the already combined flowis provided via pores and/or other openings in the drug conduit, such aspores along the walls of the conduit. In some embodiments, anintersection between the conduits comprises a porous membrane.Optionally, a flow regulator such as a valve is positioned at a locationsuitable to control an array of pores, for example allow flow throughsome pores and obstructing or partially obstructing flow through others.Such mechanism may contribute to producing a “sleeve like effect”, forexample as described herein.

In an example of a flow regime, ambient air (marked by the white arrows)enters chamber 302 through filter 318. The air flows through drugrepository 310. Drug substance-infused air, marked by the black arrows,flows from chamber 302 and into conduit 300. At a location along conduit300 more proximal to the user, ambient air may be permitted to flow intoconduit 300 through shunting conduit 320. Entry of ambient air throughshunting conduit 320 and/or the rate of ambient air flow throughshunting conduit 320 may be controlled by shunt valve 322, for examplebased on an indication of flow rate through the drug dose as provided bya flow rate sensor 314. Optionally, the drug substance-infused air(depicted as a black arrow) mixes or combines with the ambient air thatentered through shunting conduit 320, and the combined flow (marked bythe gray arrows) continues to flow through conduit 300 until exitingthrough opening 306 and into the mouth and lungs of the user.

In some embodiments, bypass valve 326 is opened to allow general ambientair (shown as a white arrow) into the device through bypass conduit 324,wherein the allowed airflow comprises a bypass airflow. Optionally, theambient flow enters mouthpiece 304 and exits it through opening 308.Optionally, flow through the conduit 300 and/or shunting conduit 320 isreduced or terminated. Optionally, the reduction or termination of flowthrough the other conduits and/or the relatively large opening 308 ofmouthpiece 304 through which the ambient air exits the device contributeto the reduction of drag forces, potentially facilitating the user'sinhalation through the device and enabling a large volume of air to passthrough to the user within a short period of time. In some embodiments,the shunting conduit 320 and the drug conduit 300 are kept separate upto the proximal aperture of the mouthpiece. Optionally, the two conduitsare completely separate, including separate mouthpiece apertures;however, it is a potential advantage to merge the two airflows earlier(e.g. at a distal region of the mouthpiece), to avoid the possibilitythat one airflow would become selectively blocked by the user's ownmouth parts.

In some embodiments, out of the total volume of air that passes throughthe inhaler device to the user during a use session, about 5%-20%,10%-50%, 30%-70% or intermediate, higher or lower ranges pass throughthe drug dose.

In some embodiments of the invention, at least one temperature sensor315 is provided at a location allowing it to estimate and/or measuretemperature at a dose cartridge (drug repository) 310. Optionally, themeasurement is made continuously, or at one or more discrete timesduring a drug substance administration regime where heat is used toextract the drug substance. Optionally, temperature distribution ismeasured among two or more regions of the dose cartridge. Optionallytemperature is measured without contacting the drug dose and withoutinterfering with airflow therethrough, for example by infrared (IR)sensing. Said sensor 315 may be positioned in the area before thecarrier airflow meets the drug cartridge. Where sensor 315 is an opticalsensor (such as an IR sensor), it is optionally configured, for example,to take readings from a field of view 315A of the dose cartridge 310.Potentially, use of an IR sensor positioned away from the drug doseitself reduces sensor degradation due, for example, to vaporcondensation and degradation of the sensitivity of sensor 315.

In some embodiments, a controller (not shown) receives the temperaturedata to provide control of heating according to a planned heatingprofile and/or as a feedback parameter indicating airflow. For example,heating is provided until a target temperature is reached, heatingamount is modulated based on a rate at which target temperature is beingapproached, and/or heating amount is modulated to maintain a targettemperature in a targeted range. This is a potential advantage, forexample to reduce variability caused by changes in available heatingpower, differences in manufacturing, and/or differences in environmentalconditions (e.g., ambient temperature and/or humidity).

In some embodiments, a controller uses received temperature data toestimate an amount of drug substance vaporized. Optionally, this alsocomprises an estimate of the amount of drug substance actually receivedby the inhaler. Optionally, this estimate is used for example, inprocess monitoring, and/or in planning the timing/dosage in the nextinhalation as a part of a regimen.

In some embodiments, temperature data is used with feedback control of aflow pattern. For example, the combined effect of air flow andtemperature define the amount of drug substance vaporized within a givenperiod. The measure of one of both the two is optionally used in realtime (i.e., during the same inhalation) to control the other and/or theoperation of the system overall. For example, under-heating of the drugdose (potentially influenced by cooling from the carrier airflow) isoptionally counteracted at least in part by reducing the fraction offlow which passes through the drug dose and/or increasing a heatingperiod. Additionally or alternatively, if high flow is detected, heatoutput is raised so that the extraction temperature remains withinspecified parameters. Similarly, over-heating/under flow are potentiallyaddressed by one or both of lowering heating energy and/or increasingthe fraction of total air flow which passes through the drug dose and/oradjusting a time period allotted for drug substance extraction or aportion thereof. It is a potential advantage to have both types ofinformation, since the cooling effects of air flow are potentiallyvariable, depending, for example, on humidity and/or air pressure; whiletemperature measurements alone do not necessarily establish that a drugsubstance is being delivered as intended.

Reference is now made to FIGS. 4A-4E, which illustrate flow regulationat various time points following an indication of inhalation, accordingto some embodiments of the invention.

The following illustrations describe flow regulation in an inhalerdevice in which drug substance is released over a certain time period,in this example over a time period of 2.9 seconds. In some embodimentsthe drug substance release time may vary (depending, for example, on thetype of drug dose, drug substance to be released, and/or the doseadministered to the user). Also, in some embodiments the drug substancerelease time is not predefined, and is dynamically adjusted during use,for example based on inhalation parameters of the user.

In some embodiments, drug substance release is activated in response toa trigger, for example a detected inhalation flow rate above a certainthreshold. Additionally or alternatively, the trigger comprisesmechanical activation (e.g. by pressing a push button) or sensingcontact with the mouthpiece. Optionally, sensing a flow of air exhaledby the user into the device is used to trigger the activation of drugsubstance release, for example by sensing a flow above a specificthreshold. Optionally, by sensing a parameter of this exhalation (e.g. apressure change, a rate of pressure change and/or a flow rate within thedevice) the user's inhalation capacity may be estimated. Such estimatemay be used to control one or more of the parameters of operation of thedevice, including for example, the duration of any part of the flowprofile, the timing and temperature of heating, a duration and/or timingof obstructing flow through the device, etc.

In FIG. 4A, illustrating flow through the device at 0.5 seconds postactivation of drug substance release, air (indicated by the whitearrows) flows into drug repository 400, and passes through it carryingthe drug substance into drug conduit 402 (now indicated by the blackarrows). In some embodiments, a sensor 404 configured along drug conduit402 senses the flow rate. Optionally, based on the indication from thesensor, valve 406 is moved to a position in which ambient flow throughshunting conduit 408 is allowed. In some embodiments, valve 406comprises a plurality of partially open configurations in which acertain rate and/or volume of flow is allowed into the device, so thatflow in excess of the target flow through the drug dose (as indicated,for example, by sensor 404) will be obtained from the atmosphere viashunting conduit 408. Optionally, valve 406 is mechanically configuredso that flow in excess of the target flow through the drug dose, asperceived by the valve itself, will be obtained via shunting conduit 408without need for sensing.

In an example, the target flow comprises a constant rate of flow throughthe drug dose, of 1 L/min for example. If the user inhales at rate of 3L/min, valve 406 will open to allow flow at a rate of 2 L/min throughshunting conduit 408.

In FIG. 4B, illustrating flow through the device at, for example, 1.3seconds post activation of drug substance release, a change in flow ratethrough the drug dose may be observed by sensor 404 and/or perceived bya mechanical valve 406. In an example, if the flow rate is lower than atarget rate of flow through the drug dose, the positioning of valve 406is dynamically adjusted to obtain less flow from the atmosphere, therebyincreasing the upcoming flow through the drug dose. In the exampledescribed above, if at this point the user inhales at a rate of 2 L/min,a rate of 1 L/min will be allowed through shunting conduit 408,maintaining the target, constant flow rate of 1 L/min through the drugdose.

In FIG. 4C, illustrating flow through the device at 2.95 seconds afteractivation of drug substance release (therefore 50 msec after drugsubstance release was terminated), valve 406 is moved to a position inwhich shunting conduit 408 is fully obstructed, causing all flow thatenters the device (for example in response to suction caused byinhalation of the user) to pass through drug conduit 402, flushing awaydrug dose residue.

In FIG. 4D, at 3.05 seconds post activation of drug substance release,optionally all flow to the user is obstructed. In some embodiments, thefull obstruction is performed for a predefined time period, for examplebetween 5 and 400 msec, or for a greater, smaller, or intermediateperiod. Additionally or alternatively, the duration of obstruction isdynamically selected and/or adjusted, for example during use, forexample based on the inhalation parameters of the user. In some cases,obstruction of flow evokes a sensory stimulus in the user's body, whichmay involve excitatory response of the respiratory muscles.

In FIG. 4E, at 3.11 seconds post activation of drug substance release,valve 406 fully opens to allow flow through conduit 402 and throughshunting conduit 408. Optionally, an additional valve 410 configured atmouthpiece 412 opens to increase a cross sectional area of a passagethrough mouthpiece 412, thereby allowing increased flow rate through themouthpiece.

In some embodiments, the sudden rise in flow rate provides an indicationto the user. Additionally or alternatively, the operational sequenceincluding relatively resisted flow (resisted due to drag forces),followed by a reduction or obstruction of flow, followed by increasedflow at relatively low resistance provides an indication to the user.Optionally, the indication notifies the user regarding the use ortreatment status, for example signaling the user to cease inhalation andoptionally remove the inhaler from the mouth. In some embodiments, anindication for example as described (or one including one or more of theoperational actions, for example a sudden obstruction of flow) isprovided during use or treatment at a time point other than the end ofthe use, for example to signal the user to breath more deeply.

A potential advantage of an operation sequence comprising a substantialreduction or obstruction of flow, followed by a rapid rise in the flowrate and/or volume may include triggering of respiratory reflexes thatmay reduce an anatomical “dead space” effect, and stimulate deep lunginhalation. Another potential advantage of an operation sequence inwhich a direct lung-device interface is obtained may include increasingthe user's compliance and reducing the need for a cognitive effort to bemade by the user, as compared to devices in which only audible and/orvisible and/or tactile indications are provided.

It is noted that the flow regulation regime and time schedule describedhereinabove in FIGS. 4A-4E is potentially advantageous in a device inwhich drug substance release comprises extraction of one or more activesubstances by heating the drug dose. For example, 1,500 μg of activeingredient are extracted from a 15,000 μg source drug dose material, andare provided over a use session of approximately 3 seconds. In anotherexample, 500 μg of active ingredient are extracted from a 15,000 μgsource drug dose material, and are provided over a use session ofapproximately 1.5 seconds.

Optionally, a target heating profile and/or a target/airflow profileincludes fluctuating operation during the drug substance extraction. Asshown, for example, in FIGS. 4A-4E, the drug substance is optionallydelivered during a heating period of 2.9 seconds. During this period,drug substance-infused vapors are optionally dynamically mixed withambient air; for example at an average ratio of about 80% air:20% drugsubstance-infused air. Optionally, this period is followed by a period(e.g., about 0.1 seconds) during which 100% of airflow is through thedrug dose; and thereafter a brief period in which airflow is at leastpartially blocked (e.g. for less than 100 msec) may take place. Finally,flow is optionally resumed for a period in which 100% ambient air isprovided (even if partially passing through a cold and potentiallydepleted dose cartridge).

This flow pattern may be depicted schematically as follows (withoutdetailing the blocking period):

-   -   (A80%, D20%) for 2.9 seconds, then D100% 100 ms, then A100% 900        ms

where A=Air (air substantially free of drug substance) and D=Drug(carrier airflow carrying drug substance).

In some alternative embodiments, a different protocol may be used, wherethe portion of carrier airflow to ambient airflow is controlled variablysuch that the concentration of drug substance received by a user variesduring extraction. For example:

-   -   [(A70%, D30%) for 200 ms, (A95%, D5%) for 200 ms], repeat until        2.9 seconds are up, then D100% 100 ms, then A100% 900 ms    -   or:    -   [(D100%) for 50 ms, (A100%) for 100 ms], repeat until 2.9        seconds are up, then D100% for 50 ms, D100% 100 ms, then A100%        900 ms

or another protocol using different ratios of A and D flow, greater,smaller, or intermediate period lengths, and/or greater, smaller, orintermediate numbers of period repetitions.

Reference is now made to FIG. 5, which is a schematic graph of a flowregime for pulmonary delivery of at least one active drug substance,according to some embodiments of the invention, as also shown, forexample, in FIGS. 4A-4E.

In the flow graph shown herein, an example for a use session over atotal duration of approximately 4-5 seconds is described. It is notedthat use sessions in accordance with some embodiments may include adifferent duration, a different target flow profile through the drugdose, a different air pulse volume, a different drug substance releaseperiod, and/or other parameters that are different than the parametersdescribed herein.

During the first 2.9 seconds, drug substance is released. The targetflow profile through the drug dose comprises a constant flow rate, inthis example of 1 L/min. A rate of ambient air flow through the inhalerfluctuates between various values, optionally in response to adynamically changing inhalation flow rate of the user. At 2.9 seconds,ambient flow is restricted, and in the shown example flow rate throughthe drug dose increases, potentially flushing drug dose residue. At 3seconds, a full obstruction of flow into the device occurs, followed at3.1 seconds by a pulse of air at a high flow rate.

In some embodiments, a targeted total volume of the air pulse and/or aduration over which the pulse is supplied to the user are selected toreduce or eliminate an effect of the anatomical dead space (a portion ofthe human airways in which gas exchange does not take place). In anadult human, the anatomic dead space is about 150 ml in volume.Accordingly, in the flow regime shown herein, an air pulse at a flowrate higher than 10 L/min is provided over a duration of about 1 second,providing a total of about 166 ml, which is a volume larger than theanatomical dead space, potentially chasing the drug substance-infusedair previously inhaled by the user deeper into the lungs.

In an example of a user inhaling at an average flow rate of 5 L/min, andassuming a constant target flow rate through the drug dose of 1 L/min,during at least 70%, 80%, 90% or intermediate, higher or lowerpercentages of a total duration of the use session the ambient flow ratewill be higher than the flow rate through the drug dose. Variousconsequences of supplying the user with ambient air flow at a ratehigher than a rate of drug substance-infused flow may include producinga deeper inhalation. A potential advantage of a deeper inhalation mayinclude reducing an amount of drug substance that is exhaled by theuser. Optionally, in such a case, more drug substance is absorbed in thelungs. Optionally, less drug substance is released to environment.

Optionally, a time period in which the flow rate of drugsubstance-infused air to the user may be higher than the flow rate ofambient air to the user includes the time period in which ambient flowis obstructed to cause flushing of the drug substance, and flow ratethrough the drug dose is increased.

Reference is now made to FIG. 6, which is a schematic cross sectionshowing an air flow regime in a conduit configured for reducingadherence of drug dose residue to the inner walls of the conduit,according to some embodiments of the invention.

In some embodiments, entry of ambient air flow into the drug conduit 604(e.g. from a shunting conduit) produces a sleeve like effect within thedrug conduit, in which flow 600 that is closer to a central longitudinalaxis of the conduit comprises a drug substance concentration that ishigher than a drug substance concentration in flow 602 along thecircumference of the conduit. Optionally, the drug substanceconcentration decreases in a radially outward direction.

Optionally, obtaining the sleeve like effect includes controllingambient air flow into conduit 604, such that ambient flow enters from aplurality of directions around the conduit 604, optionally at equalrates from all directions, such that the chance for turbulence isreduced or minimized.

A potential advantage of the sleeve-like effect may include reducingadherence of the drug dose and/or extracted drug substance(s) to thewalls of the conduit. This may be especially advantageous when theadministered drug substance(s) and/or products of the drug substanceextraction process have a tendency to stick to the conduit walls. In anexample, when the drug dose comprises plant material such as cannabis orPapaver somniferum, products of the extraction process (such as productsof vaporization) may include oily and/or viscous substances, such asoily THC, opium latex and/or other substances which may adhere to thewalls of the conduit. In some cases, adherence to the walls may resultin the delivery of lesser amounts than the ones administered to theuser. In some cases, materials may build up on the conduit walls andpotentially interfere with the flow. In some cases, build up may affectthe accuracy of flow rate measurement, for example if occurring at alocation of the sensor. Optionally, the sleeve-like effect reduces oneor more of the risks described herein.

In some embodiments, a sleeve-like effect takes place in other portionsand/or components of the inhaler device, such as the mouthpiece.Optionally, a “double sleeve” effect takes place when ambient airflowing through a bypass conduit meets the combined flow. Optionally,the double sleeve effect is observed at and/or in proximity to themouthpiece, optionally at the opening of the drug conduit near or withinthe mouthpiece.

Reference is now made to FIG. 7, which is a flow chart of a mechanicaloperation of an inhaler device, according to some embodiments of theinvention.

In some embodiments, operation of an inhaler device to provideflow-controlled pulmonary delivery of a drug substance to a user isperformed according to one or more of the steps described herein.

In some embodiments, inhalation and/or one or more parameters ofinhalation are detected, including, for example, one or more of: flowrate, volume, velocity, pressure and/or other parameters, optionally byone or more sensors (block 700). Optionally one or more or all of theparameters are detected and/or are used to estimate one or moreparameters of airflow near or through a dose cartridge.

In some embodiments, a controller receives input from the one or moresensors, and if the initial activation conditions are met (e.g. theinhalation flow rate is higher than a threshold), the controlleractivates drug substance release (block 702). Optionally, activation ofdrug substance release comprises heating a drug dose to release one ormore drug substances; for example, by passing an electric currentthrough an electrically resistive element in heating proximity to thedose cartridge or incorporated therein. Optionally, the resistiveheating element is arranged to heat the drug dose without blockingairflow therethrough. For example, the resistive heating element allowsairflow to enter and/or leave via at least 25% of the surface area of aface of the drug dose pallet, at least 33%, at least 50%, or via anotherlarger, smaller, or intermediate relative surface area of a drug dosepallet face.

In an embodiment, heat is applied to plant material, for examplecannabis, and air flow through the heated material evacuates one or moreactive substances such as THC from the cannabis. Optionally, the plantmaterial is contained within a cage-like wire structure, which is heatedto vaporize the active substances. In some embodiments, extractionparameters such as a temperature profile of the heated plant material, aduration of heating, an amount of plant material being heated and/orother parameters of extraction may affect flow through the drug dose. Insome embodiments, when drug substance release involves heating of thedrug dose, a rate of ambient air flow that diffuses with the flow thatpassed through the drug dose, such as ambient air entering through ashunting conduit, is selected and/or modified to be high enough to cooldown the heated flow that passed through the drug dose, reducing atemperature of the flow before the flow reaches the user.

In some embodiments, based on an indication received from the sensors,the controller operates a regulating mechanism to provide controlledambient flow into the device. In some embodiments, the regulatingmechanism comprises a plurality of valves, which may be operatedseparately from each other and/or simultaneously. In some embodiments, aplurality of valves such as 2, 4, 6 or an intermediate, larger, orsmaller number of shutter valves are configured on a rotatable discshaped element, positioned in communication with one or more conduitssuch as the drug conduit, shunting conduit, and/or bypass conduit of theinhaler device. Optionally, the valves are holes in the rotatable disc,extending between proximal and distal faces of the disc. An example forsuch rotatable disc is described in further detail in connection withFIGS. 9A-9B and 10A-10C.

In some embodiments, the controller turns the disc element to allow flowof ambient air into the device (block 704), such as flow through theshunting conduit. Optionally, an extent of overlap between a valveopening and a conduit opening is adjusted by rotating the disc, to allowa targeted volume of flow to pass through the valve opening. Optionally,an arrangement of the valves on the disc is designed so that when afirst valve is open (or partially open), one or more other valves orclosed, or vice versa. Alternatively, arrangement of the valves is ontwo or more discs, optionally allowing separate control of the valvesfor each of at least one second conduit and at least one third conduit.

In some embodiments, the valves are arranged relative to each otherand/or relative to the conduits they are in communication with toprovide a full obstruction of the flow to the user, for example when thedisc is rotated to a certain angular position (block 706).

In some embodiments, optionally following obstruction of flow, thecontroller turns the disc to a position in which a pulse of flow can beprovided to the user (block 708), for example by fully opening valvesthat block the bypass conduit(s). Optionally, valves that block the drugconduit(s) and/or valves that block the shunting conduit(s) may beopened as well.

Reference is now made to FIG. 8, which illustrates a longitudinal crosssection view of an inhaler device, according to some embodiments of theinvention.

In FIG. 8, the white arrows indicate ambient air flow, the black arrowsindicate flow through the drug dose, and the gray arrows indicate acombination of ambient flow that joined the flow that passed through thedrug dose.

In the structure shown herein, a flow sensor 800 is positioned at apoint along drug conduit 802, to sense the flow rate through the drugconduit. This point may be distal to the user. Optionally, the sensorcan be configured at any point axially along drug conduit 802 which,along the flow path, located before (i.e. distal to) a first point inwhich shunting air is allowed to flow into the drug conduit, such as ata junction 806 between a shunting conduit 804 and the drug conduit.Optionally, junction 806 is positioned closer to a proximal opening 816of drug conduit 802, such as within mouthpiece 810. A potentialadvantage of a junction between the shunting conduit and the drugconduit which is located at a relatively distal point along the drugconduit (i.e. farther away from the user end) may include reducing theamount of drug dose residue that adheres to the walls of the drugconduit.

In some embodiments, drug substance-infused air enters chamber 808, fromwhich it enters drug conduit 802. Optionally, chamber 808 is a part ofthe drug conduit 802 (for example by the drug conduit widening in thedistal direction and/or at a distal portion of it).

In some embodiments, constant movement of the drug substance-infused airthrough the chamber and into the drug conduit is maintained. A potentialadvantage of continuously moving flow may include reducing a risk ofcondensation of drug dose residues and/or the one or more released drugsubstances. Alternatively, at least some volume of drugsubstance-infused air is allowed to accumulate within the chamber, forexample to cool it down before it enters the drug conduit and deliveredto the user.

In some embodiments, one or more bypass conduits 812 allow for ambientair flow into the device. Optionally, an opening 814 of bypass conduit812 is located adjacent opening 816 of drug conduit 802, both beingproximal to the user. Optionally, both openings 814 and 816 lead toproximal opening 818 of mouthpiece 810. As previously referred toherein, when ambient flow through bypass conduit 812 is enabled, dragforces are reduced and a resistance the user encounters duringinhalation decreases, for example as compared to a state in which onlyflow through drug conduit 802 was allowed.

Reference is now made to FIGS. 13A-13D, which schematically illustrate avalve apparatus 1300 comprising an outer tube 1302 having valveapertures 1314, 1316, which are rotatable with respect to conduitapertures 1310, 1312 of internal tube 1301, for a performing a sequenceof conduit openings and closures, according to some embodiments of theinvention.

In some embodiments, internal tube 1301 comprises one or more firstjunctions, each between a drug conduit 1320 and a respective shuntingconduit 1330. In some embodiments, internal tube 1301 comprises one ormore second junctions, each between the drug conduit 1320 and arespective bypass conduit 1340. Additionally or alternatively, in someembodiments, bypass conduit 1340 leads directly to a mouthpieceaperture, for example, the aperture having diameter 1341. The internaltube 1301 is positioned within external tube 1302. Apertures 1314, 1316of external tube 1302 correspond to apertures 1310, 1312 of the internaltube 1301, leading into the shunting and bypass conduits 1330, 1340,respectively.

In some embodiments, both the internal and external tubes 1301, 1302 arepositioned along a longitudinal axis defined by the drug conduit 1320and extend between a dose unit held by a holder of the inhaler deviceand a mouthpiece. The direction of air flow through drug conduit 1320 isdepicted by arrow 1325.

The flow of air into the shunting and bypass conduits is optionallycontrolled by the relative position of the apertures 1310 with respectto apertures 1314 (these apertures working together comprise a shuntvalve for the shunt conduit 1330, in some embodiments); and/or apertures1312 with respect to apertures 1316 (these apertures working togethercomprise a bypass valve for the bypass conduit 1340, in someembodiments). Control of relative position comprises, for example,rotating (for example, rotating by a motor under control of acontroller) at least one of the tubes 1301, 1302 around the longitudinalaxis, and/or adjusting the relative positions of the tubes 1301, 1302along the longitudinal axis (for example, by a motor under control of acontroller). Optionally, two external (or internal) tubes are providedpotentially allowing separate control of air flow into the shunting andbypass conduits. Optionally, any or all of the apertures and conduits1310, 1312, 1314, 1314, 1330, 1340 are provided in sets, for examplesets of two, three (illustrated in FIGS. 13A-13D), four or more for eachelement.

In some embodiments, valve apertures 1314, 1316 are positionablerelative to conduit apertures 1310, 1312 (respectively) to open andclose (or partially close/open) air flow into the conduits 1330, 1340.Optionally, the relative positionings and movements of apertures is suchthat when the shunting conduits 1330 are at least partially open, flowthrough the bypass conduits 1340 is blocked. Contrariwise, in someembodiments, opening the bypass conduits 1340 closes the shuntingconduits 1330. Alternatively, complete opening of one valve accompaniescomplete closure of the other, with partial closure/opening of eachvalve during transitional positions.

In some embodiments, the bypass conduit valve apertures 1316 are on oneexternal tube and the shunting conduit valve apertures 1314 are onanother external tube. This potentially allows, for example, opening theshunting and bypass conduits independently one from the other, inaddition to the positions afforded by the example shown in FIGS.13A-13D.

In some embodiments, any or all of the “all conduits at least partiallyopen”, “only a portion of the conduits at least partially open” and “allconduits closed” alternatives are achieved by another arrangement. Forexample, rotational movement at one relative longitudinal position ofthe two tubes opens only one set of valves at a time, and relativelongitudinal translation of the tubes at least partially opens(optionally, opens or closes) both sets of valves at once.

FIGS. 13C-13D show cross sectional views taken along a longitudinal axisof FIG. 13A, illustrating inner portions of conduits 1330, 1340 incommunication with drug conduit 1320.

Flow from the shunting conduits 1330 joins flow in the drug conduit 1320before a second aperture having a second diameter 1331 (and optionallyjoins after a first aperture having a first diameter 1321). Optionally,flow from the bypass conduits 1340 joins before a third aperture havinga third diameter 1341. Additionally or alternatively, at least for aportion of an inhalation event, flow from the bypass conduits 1340 iskept separate from the drug conduit flow; for example, operatedseparately, and/or spatially separated. Optionally separation is by apartition extending to the mouthpiece, or by arranging flow so that alaminar effect is created substantially without mixing. Optionally, thesecond diameter 1331 is small enough to limit air flow via the devicewhen the bypass conduits 1340 are closed. Potentially, this encourages auser to inhale with force.

Optionally, the third diameter 1341 is significantly larger than thesecond diameter 1331. Thus, when air is allowed to flow through thebypass conduits 1340, it does not experience the drag applied by thesecond aperture but rather flows relatively freely into the lungs.

Reference is now made to FIGS. 9A-9B, which are a front view crosssection of a mouthpiece of an inhaler device (FIG. 9A) and alongitudinal cross section of the mouthpiece (FIG. 9B), according tosome embodiments of the invention.

In the cross section of FIG. 9A, rotatable disc 900 is turned to aposition in which all conduits of the inhaler device are open to allowflow through, as all valve openings in disc 900 overlap with the distalopenings of the conduits, through which air flow is allowed into theconduits.

Additionally or alternatively, in some embodiments, a valve may bepositioned at a proximal end of a conduit. Optionally, a first valve isconfigured at a distal opening of a conduit, and a second valve isconfigured at a proximal end of a conduit, the valves operatedrespectively to provide a local regulation of flow through the conduit.Additionally or alternatively, a valve may be positioned at any pointalong a conduit.

The structure shown herein comprises three shunting conduits 902(alternatively referred to as a single shunting conduit comprising threetracts), connected to a drug conduit 904 (a proximal opening of which isshown), and three bypass conduits 906 (alternatively referred to as asingle bypass conduit comprising three tracts), extending to a proximalopening of the mouthpiece.

In some embodiments, disc 900 is a cogwheel that can be rotated by amotor, optionally in response to a signal received from the controller.In the configuration described herein, rotation of disc 900simultaneously changes the relative positioning for at least a part ofthe valve openings on the disc, for example openings allowing flowthrough the shunting conduit(s)/tract(s). Optionally, the valve openingsare arranged so that all conduits of a certain function (e.g. shuntingconduits) are opened and/or closed at the same time. A potentialadvantage of adjusting all valve openings by a single movement mayinclude simplifying the mechanical operation of the device, reducing theneed for complex control over the valves, and/or reducing the need forsmall components, thereby potentially reducing a risk of device failureand/or potentially reducing its cost of manufacture. Alternatively, insome embodiments, one or more valves are operable independently of othervalves.

In some embodiments, disc 900 is aligned with respect to drug conduit904. Optionally, the rotation axis of disc 900 are parallel to (or, insome embodiments, united with) a longitudinal axis of drug conduit 904.

In some embodiments, the valve openings of disc 900 are symmetricallyarranged with respect to drug conduit 904, for example with respect to aproximal opening of the drug conduit. Alternatively, an arrangement ofthe valve openings is asymmetrical.

A longitudinal cross section of the mouthpiece of FIG. 9A is illustratedin FIG. 9B. The proximal opening 908 of drug conduit 904 is shown to bepositioned a distance away from a full opening 910 of the mouthpiece,for example to enable parallel flow of the ambient air that entersthrough bypass conduit 906, at least during some stages of operation ofthe device.

Reference is now made to FIG. 15, which schematically illustrates aninhaler 1500 for optionally simultaneous administration of substancesfrom a plurality of dose cartridge chambers 1520, 1530 in acorresponding plurality of drug conduits 1522, 1532, according to someembodiments. Inhaler 1500 comprises a carousel type magazine 1510 forstoring a plurality of dose cartridges before and/or after use.

In some embodiments, a plurality of separate drug conduits 1522, 1532are provided, each comprising a dose cartridge chamber (holder) 1520,1530. In some embodiments, a dose cartridge chamber defines a cartridgeposition in a carrier airflow of a drug conduit by where it positions adose cartridge when a dose cartridge is in the cartridge chamber,prepared for inhalation. Optionally, dose cartridges 1500C, 1500D aredrawn from a single carousel-type magazine 1510 or other cartridgemagazine. Alternatively, a plurality of magazines is provided. Cartridgedrawing is optionally simultaneous, sequential and/or separatelyoperated altogether, and optionally while the cartridge magazine(s)remain in a single position, or with movement of the magazine 1510 (e.g.rotation) between draws.

In some embodiments, flow through the drug conduits 1522, 1532 is atleast partially regulated by providing a shunt conduit 1515 in flowcommunication with the drug conduits 1522, 1532. The total flow of air1509 through the device due to inhalation from a mouthpiece 1502 isoptionally divided among all conduits (for example by the sizing and/orsize adjustment of conduit diameters and/or valves), such that theportion of airflow through each drug conduit 1522, 1532 is adjusted tobe within a targeted carrier airflow profile. Remaining airflow isoptionally directed through the shunt conduit 1515. Optionally, the drugconduits are operated separately (for example, only one is operated, orboth are operated in sequence).

Optionally, sensors 1540 providing data (e.g. airflow and/or temperaturedata indicative of airflow and/or temperature at the dose cartridgesduring operation) for control are optionally positioned near or via oneor more of the dose cartridges 2300C, 2300D. Control optionallycomprises adjustment of airflow (for example, by adjustment of a valveor aperture position) such that both dose cartridges 2300C, 2300Dsimultaneously experience airflow 1505, 1507 within a given range.Alternatively, adjustment is such that a part of the airflow sequence iscontrolled with respect to a first chamber 1520, while another part iscontrolled according to second chamber 1530. Optionally, in somesessions, only one of chambers 1520, 1530 is used.

In some embodiments, a plurality of tracts for shunting conduit 1515 isprovided, for example, one in separate association with each of the drugconduits 1522, 1532. Optionally, the air flowing in each of the drugconduits 1522, 1532 is combined only at the mouthpiece. A potentialadvantage of this is to allow separate control of airflow through eachdose cartridge. It is also to be understood that a bypass conduit isalso provided in some embodiments which is configured for use with aplurality of drug conduit tracts.

In some embodiments, a plurality of chambers (holders) 1520, 1530 areprovided within a single tract of a drug conduit. Optionally,differential control of drug substance vaporization comprisesdifferential heating of drug doses contained in each holder.

Reference is now made to FIGS. 10A-10C, which are isometric, partiallycross-sectional views of the mouthpiece during operating stages of theinhaler device, according to some embodiments of the invention.

In FIG. 10A, disc 1000 is rotated to a position in which a distalopening of bypass conduit 1002 abuts against disc 1000, and the flowthrough bypass conduit 1002 is blocked. A partial overlap exists betweenvalve opening 1004 and a distal opening of shunting conduit 1006,allowing limited air flow into shunting conduit.

In FIG. 10B, disc 1000 is rotated, for example, in the direction shownby arrow 1008, to a position in which bypass conduit 1002 is stillobstructed, a full overlap exists between valve opening 1004 andshunting conduit 1006, allowing free flow into the shunting conduit1006.

In FIG. 10C, disc 1000 is once again rotated in the direction of arrow1008 to a position in which a valve opening 1010 overlaps with a distalopening of bypass conduit 1002, allowing flow through the bypassconduit, while obstructing flow through shunting conduit 1006.

Reference is now made to FIG. 11, which shows a partial cross section ofan inhaler device, according to some embodiments of the invention.

In some embodiments, device 1100 is encased within an external housing1102, optionally comprising a circular, disc-like shape. Alternatively,in some embodiments, housing 1102 comprises other shapes, such as arectangular box shape, a cylindrical shape, and/or other shapes suitablefor gripping by the user.

In the structure shown herein flow sensor 1104 is positioned at a distalend of drug conduit 1106. Drug conduit 1106 extends in a proximaldirection up to mouthpiece 1108. A proximal opening 1112 of drug conduit1106 is centralized with a proximal opening of mouthpiece 1108, which isto be engaged by the mouth of the user.

A valve disc (optionally configured as a cogwheel, encased within aninternal housing in this Figure), configured for controlling flowthrough the conduits of the device, is operably coupled to a gear motor1110. Optionally, gear motor 1110 is operated by a controller, locatedfor example within a housing 1116.

In some embodiments, the device comprises a drug cartridge, for exampleshaped as a disc 1118 loaded with one or more drug dose units.Optionally, the controller is configured to actuate movement of thedisc, for example prior to a use session and/or between use sessions.

In some embodiments, the device comprises a lever 1120 for manuallyloading or unloading a drug cartridge (as a disc 1118 in the shownexample).

Reference is now made to FIG. 12, which is a schematic illustration ofcomponents of a mechanically operated flow control system, for exampleas incorporated within an inhaler device, according to some embodiments.Reference is also made to FIG. 14, which is a schematic illustration ofanother mechanically operated flow control system, according to someembodiments.

In some embodiments, flow control is at least partially provided by amechanical element, for example a check valve. Some embodiments do notinvolve electrical airflow control, such as by a controller and/or anair flow sensor, and are controlled and/or operated solely by purelymechanical elements, for example in response to pressure changes.

In this configuration, a check valve, for example a ball check valve1200 (shown in an enlarged view as well), is positioned in communicationwith chamber 1202 (and/or with drug conduit 1204). Optionally, checkvalve 1200 allows shunting air flow into the inhaler device (to join theflow that passed through the drug dose) in response to pressuredifferences. In some embodiments, when a user inhales through thedevice, a pressure difference is created between chamber 1202 and theenvironment. Optionally, the pressure difference is large enough tocause valve 1200 to open and allow flow of ambient air into the device.Optionally, the extent of opening of check valve 1200 varies in responseto a change in the pressure gradient, so that equilibrium is reached.For example, if the gradient increases (i.e. the pressure in the chamberdecreases), the opening will expand to allow more flow to enter, therebymaintaining a constant pressure within the chamber.

In some embodiments, flow through the drug dose is at least partiallyresisted, for example by shaping and/or sizing the drug conduit and/orchamber to resist flow, to allow a pressure difference between thechamber and the environment to form.

In some embodiments, a normally open reverse check or flutter valve 1402is provided in the drug conduit which is configured to partially close,or at least momentarily close (for example, flutter) as a rate of flowthrough it increases. In some embodiments, this increases resistance inthe carrier airflow pathway, potentially allowing flow at a shuntingconduit 1400 to increase, thereby resulting in a greater ratio ofshunting to carrier airflow at mouthpiece 1404. Optionally, the normalratio of intake flow resistances shunting conduit 1400 and at valve 1402is set (for example, by size or shape) so that the majority of flowintake is through the extraction pathway until closure of valve 1402occurs. Optionally, check valve 1200 is used in conjunction with valve1402, so that both pathways are mechanically regulated.

Potentially, activation of one or both of valves 1200, 1402 also servesas feedback to a user (e.g., due to noise of valve operation) that arate of inhalation is sufficient and/or excessive.

In some embodiments, maintaining a constant pressure within the chamberproduces a constant flow rate through the drug dose, even if innerpressure differences (e.g. between the chamber and the drug conduit)vary as a result of the naturally varying inhalation flow rate of thepatient. Optionally, the targeted flow profile is configured and/orestimated according to a geometry of the chamber and/or conduits.

In some embodiments, flow through the bypass conduit is controlled by atimed spring valve, for example opening in a set time after activationof the device, for example to allow rapid flow to the user.

As used herein with reference to quantity or value, the term “about”means “within ±10% of”.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean: “including but not limited to”.

The term “consisting of” means: “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

The words “example” and “exemplary” are used herein to mean “serving asan example, instance or illustration”. Any embodiment described as an“example” or “exemplary” is not necessarily to be construed as preferredor advantageous over other embodiments and/or to exclude theincorporation of features from other embodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features except insofar as such features conflict.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

Throughout this application, embodiments of this invention may bepresented with reference to a range format. It should be understood thatthe description in range format is merely for convenience and brevityand should not be construed as an inflexible limitation on the scope ofthe invention. Accordingly, the description of a range should beconsidered to have specifically disclosed all the possible subranges aswell as individual numerical values within that range. For example,description of a range such as “from 1 to 6” should be considered tohave specifically disclosed subranges such as “from 1 to 3”, “from 1 to4”, “from 1 to 5”, “from 2 to 4”, “from 2 to 6”, “from 3 to 6”, etc.; aswell as individual numbers within that range, for example, 1, 2, 3, 4,5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein (for example “10-15”, “10to 15”, or any pair of numbers linked by these another such rangeindication), it is meant to include any number (fractional or integral)within the indicated range limits, including the range limits, unlessthe context clearly dictates otherwise. The phrases“range/ranging/ranges between” a first indicate number and a secondindicate number and “range/ranging/ranges from” a first indicate number“to”, “up to”, “until” or “through” (or another such range-indicatingterm) a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numbers therebetween.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting. In addition, any priority document(s) of this applicationis/are hereby incorporated herein by reference in its/their entirety.

What is claimed is:
 1. An inhaler device for delivery of at least oneactive substance to an inhaling user, the inhaler device comprising: afirst conduit for conducting airflow to an opening from which the userinhales; a valve positioned and configured to affect flow of ambient airinto the first conduit; a controller configured to control release ofthe at least one active substance to be carried by the airflow to theinhaling user, the controller further configured to control the valve togenerate a pattern of airflow and active substance delivery modulations,the pattern including: (a) delivering the active substance via theairflow followed by substantially stopping active substance delivery andreducing a total rate of airflow to the user for an intermediate period,and then (b) increasing the airflow without resuming active substancedelivery to a rate or volume sufficient to be sensed by the inhalinguser.
 2. The inhaler device according to claim 1, wherein the controlleroperates the valve to increase the airflow to allow inhalation of avolume of air which is equal to or larger than a volume of an anatomicdead space of the inhaling user.
 3. The inhaler device according toclaim 1, wherein the controller is configured to time the increase inairflow towards the end of a use session during which the user inhaledfrom the inhaler device thereby indicating to the user that delivery hasbeen completed.
 4. The inhaler device according to claim 1, wherein thevalve is positioned in the first conduit.
 5. The inhaler deviceaccording to claim 1, comprising a holder configured to position a dosecartridge from which the active substance is released at a dosecartridge position defined by the holder within the airflow passingthrough the first conduit.
 6. The inhaler device according to claim 5,comprising a second conduit, pneumatically coupled to the first conduit,for conducting a shunting airflow to the opening from which the userinhales without passing the shunting airflow through the dose cartridgeposition.
 7. The inhaler device according to claim 6, wherein the valveis positioned in the second conduit.
 8. The inhaler device according toclaim 6, wherein the at least one valve is positioned along the secondconduit and configured to limit a rate of the shunting airflow.
 9. Theinhaler device according to claim 1, wherein the at least one activesubstance comprises a drug.
 10. The inhaler device according to claim 1,wherein the at least one active substance comprises THC.
 11. The inhalerdevice according to claim 1, wherein the at least one active substancecomprises nicotine.
 12. The inhaler device according to claim 1,comprising at least one sensor positioned and configured to detect arate of the airflow, wherein the controller is configured to operate thevalve based on an indication of a rate of the airflow provided by thesensor.
 13. The inhaler device according to claim 1, comprising aheating assembly configured to heat material of a dose cartridgecomprising the at least one active substance to release the at least oneactive substance by vaporization.
 14. The inhaler device according toclaim 1, wherein the controller is configured to operate the valveaccording to a predefined target airflow profile.
 15. The inhaler deviceaccording to claim 1, wherein the controller is configured to controlairflow during delivery of the active substance to maintain a constantairflow rate selected from the range of 0.5 L/min-2.5 L/min.
 16. Theinhaler device according to claim 1, wherein the intermediate period isbetween 5 and 400 msec.
 17. The inhaler device according to claim 1,wherein a time period during which delivery of the active substancetakes place is between 1.5 seconds-3 seconds long.
 18. A method fordelivering to an inhaling user at least one active substance,comprising: during a first inhalation period, delivering the at leastone active substance via airflow to the inhaling user; substantiallystopping delivery of the at least one active substance and reducing atotal rate of the airflow for an intermediate inhalation period; andduring a final inhalation period, increasing the airflow withoutresuming active substance delivery to a rate or volume sufficient to besensed by the inhaling user.
 19. The method according to claim 18,wherein airflow during the first inhalation period is at a constant rateselected from the range of 0.5 L/min-2.5 L/min.
 20. The method accordingto claim 18, wherein during the final inhalation period the airflow isincreased to a volume which is equal to or larger than a volume of ananatomic dead space of the inhaling user.
 21. The method according toclaim 18, wherein reducing a total rate of the airflow comprisesobstructing the airflow for the intermediate inhalation period.
 22. Themethod according to claim 21, wherein obstructing is for a time periodbetween 5 and 400 msec.
 23. The method according to claim 18, whereindelivering during the first inhalation period is for a time period ofbetween 1.5 seconds-3 seconds.
 24. The method according to claim 18,wherein increasing the airflow rate or volume is performed at the end ofa use session during which the user inhaled from the inhaler device.